天然产物跨血脑屏障胶质瘤纳米递送：从屏障异质性到策略设计

The blood–brain barrier (BBB) represents a formidable challenge in the treatment of neurological disorders, as it restricts the passage of most therapeutic agents into the central nervous system (CNS). Research in brain-targeted delivery strategies and explore in natural products for BBB modulation have opened new avenues for effective CNS drug delivery. This review highlights the latest developments in molecular-based delivery systems, cell-based approaches, physical techniques, toxicity concerns, clinical trials and artificial intelligence (AI) -driven modeling for brain-targeted drug delivery. Additionally, it examines the role of natural products, particularly aromatic resuscitation medicines, in enhancing BBB permeability through modulating tight junction proteins and inhibiting efflux transporters. It is emphasized that the integration of natural products with modern drug delivery systems offers promising opportunities for the development of novel brain-targeted therapies. However, challenges related to the complexity and variety of natural product compositions must be addressed to fully realize their potential. This review underscores the importance of continued research into the molecular mechanisms underlying BBB modulation and natural product-mediated nano-delivery strategies for CNS disorders.

Simple Summary Glioma is a type of cancer that is the most common primary brain tumor in adults. The prognosis is often unfavorable despite early detection and treatment. Therefore, it is necessary to search for novel therapeutic approaches, new therapeutic agents and their delivery systems. Compounds derived from plants: orientin, actioside, curcumin, and bisdemethoxycurcumin, were put in liposomes. Then, the liposomes were tested for their anticancer activity on gliomas cell lines. It was found that all the compounds were active, with acteoside showing the highest activity. Additionally, a combination of the compounds was proven to be more active than the single components. Abstract Glioblastoma (GBM) is the most common malignant neoplasm in adults among all CNS gliomas, with the 5-year survival rate being as low as 5%. Among nanocarriers, liposomal nanoformulations are considered as a promising tool for precise drug delivery. The herein presented study demonstrates the possibility of encapsulating four selected natural compounds (curcumin, bisdemethoxycurcumin, acteoside, and orientin) and their mixtures in cationic liposomal nanoformulation composed of two lipid types (DOTAP:POPC). In order to determine the physicochemical properties of the new drug carriers, specific measurements, including particle size, Zeta Potential, and PDI index, were applied. In addition, NMR and EPR studies were carried out for a more in-depth characterization of nanoparticles. Within biological research, the prepared formulations were evaluated on T98G and U-138 MG glioblastoma cell lines in vitro, as well as on a non-cancerous human lung fibroblast cell line (MRC-5) using the MTT test to determine their potential as anticancer agents. The highest activity was exhibited by liposome-entrapped acteoside towards the T98G cell line with IC50 equal 2.9 ± 0.9 µM after 24 hours of incubation. Noteworthy, curcumin and orientin mixture in liposomal formulation exhibited a synergistic effect against GBM. Moreover, the impact on the expression of apoptosis-associated proteins (p53 and Caspase-3) of acteoside as well as curcumin and orientin mixture, as the most potent agents, was assessed, showing nearly 40% increase as compared to control U-138 MG and T98G cells. It should be emphasized that a new and alternative method of extrusion of the studied liposomes was developed.

Glioblastoma (GBM) is one of the most aggressive malignant tumors with an overall dismal survival averaging one year despite multimodality therapeutic interventions including surgery, radiotherapy and concomitant and adjuvant chemotherapy. Few drugs are FDA approved for GBM, and the addition of temozolomide (TMZ) to standard therapy increases the median survival by only 2.5 months. Targeted therapy appeared promising in in vitro monolayer cultures, but disappointed in preclinical and clinical trials, partly due to the poor penetration of drugs through the blood brain barrier (BBB). Cancer stem cells (CSCs) have intrinsic resistance to initial chemoradiation therapy (CRT) and acquire further resistance via deregulation of many signaling pathways. Due to the failure of classical chemotherapies and targeted drugs, research efforts focusing on the use of less toxic agents have increased. Interestingly, multiple natural compounds have shown antitumor and apoptotic effects in TMZ resistant and p53 mutant GBM cell lines and also displayed synergistic effects with TMZ. In this review, we have summarized the current literature on natural products or product analogs used to modulate the BBB permeability, induce cell death, eradicate CSCs and sensitize GBM to CRT.

Glioma is one of the most perplexing cancers because of its infiltrating nature, molecular signaling, and location in central nervous system. Blood–brain barrier acts as a natural barrier to the glioma making it difficult to access by conventional chemotherapy. Clinicians are using natural compounds or their derivatives for several diseases including different cancers. However, the feasibility of using natural compounds in glioma is not explored in details. Natural compounds can act over a wide variety of signaling pathways such as survival and metabolic pathways and induce cell death. Some of the natural agents have additional benefits of crossing biological barriers such as blood–brain barrier with ease having few or no impact on the surrounding healthy cells. All of these benefits make natural compounds a prospective candidate for the glioma management. This article evaluates the benefits of using natural compounds for glioma therapy and their possible mechanism of actions. We have discussed the natural compounds assessed currently for glioma therapy and proposed a few novel natural compounds with potential antiglioma effect based on their mechanism of action.

The malignant brain cancer, glioblastoma multiforme (GBM), is heterogeneous, infiltrative, and associated with chemo- and radioresistance. Despite pharmacological advances, prognosis is poor. Delivery into the brain is hampered by the blood-brain barrier (BBB), which limits the efficacy of both conventional and novel therapies at the target site. Current treatments for GBM remain palliative rather than curative; therefore, innovative delivery strategies are required and nanoparticles (NPs) are at the forefront of future solutions. Since the FDA approval of Doxil® (1995) and Abraxane (2005), the first generation of nanomedicines, development of nano-based therapies as anti-cancer treatments has escalated. A new generation of NPs has been investigated to efficiently deliver therapeutic agents to the brain, overcoming the restrictive properties of the BBB. This review discusses obstacles encountered with systemic administration along with integration of NPs incorporated with conventional and emerging treatments. Barriers to brain drug delivery, NP transport mechanisms across the BBB, effect of opsonisation on NPs administered systemically, and peptides as NP systems are addressed.

The Glioblastoma Multiforme (GBM; grade IV astrocytoma) exhort tumor of star-shaped glial cell in the brain. It is a fast-growing tumor that spreads to nearby brain regions specifically to cerebral hemispheres in frontal and temporal lobes. The etiology of GBM is unknown, but major risk factors are genetic disorder like neurofibromatosis and schwanomatosis which develop the tumor in the nervous system. The management of GBM with chemo-radio therapy leads to resistance and current drug regimen like Temozolomide (TMZ) is less efficacious. The reasons behind failure of drugs are due to DNA alkylation in cell cycle by enzyme DNA guanidase and mitochondrial dysfunction. Naturally occurring bio-active compounds from plants known as phytochemicals, serve as vital sources for anti-cancer drugs. Some typical examples include taxol analogs, vinca alkaloids such as vincristine, vinblastine, podophyllotoxin analogs, camptothecin, curcumin, aloe emodin, quercetin, berberine e.t.c. These phytochemicals often act via regulating molecular pathways which are implicated in growth and progression of cancers. However the challenges posed by the presence of BBB/BBTB to restrict passage of these phytochemicals, culminates in their low bioavailability and relative toxicity. In this review we integrated nanotech as novel drug delivery system to deliver phytochemicals from traditional medicine to the specific site within the brain for the management of GBM.

Glioblastoma (GBM) is a prevalent type of malignancy within the central nervous system (CNS), associated with a poor prognosis. The standard treatment for GBM includes surgical resection of the tumor, followed by radiotherapy and chemotherapy; yet despite these interventions, overall treatment outcomes remain suboptimal. The blood-brain barrier (BBB), which plays a crucial role in maintaining the stability of brain tissue under normal physiological conditions of the CNS,also poses a significant obstacle to the effective delivery of therapeutic agents to GBM. Recent preclinical studies have demonstrated that nanomedicine delivery systems (NDDS) offer promising results, demonstrating both effective GBM targeting and safety, thereby presenting a potential solution for targeted drug delivery. This review explores the various strategies employed in preclinical studies to overcome the BBB for drug delivery. Subsequently, the results of clinical translation of NDDS has been summarized, highlighting the progress made. Finally, we discuss potential strategies for advancing NDDS development and accelerating their translational research through well-designed clinical trials in GBM therapy.

Glioma is the most common and aggressive primary intracranial tumor within the central nervous system. The blood-brain barrier (BBB) has been a great hurdle for an effective glioma treatment. To effectively treat glioma, various strategies have been applied to deliver drugs to the brain by crossing the BBB. Nanocarrier-mediated drug delivery is emerging as an effective and noninvasive system to treat glioma, showing great potential in glioma therapy. In this review, we will provide a comprehensive overview on nanocarrier-mediated drug delivery and related glioma therapy. Following an initial overview of the BBB and blood-brain-tumor barrier (BBTB) structure and characteristics, nanocarrier-mediated drug delivery strategies (liposomes, micelles, inorganic systems, polymeric nanoparticles, nanogel system, biomimetic nanoparticles, and exosomes) for crossing the BBB are discussed. Finally, nanotherapeutic techniques (imaging-mediated chemotherapy, photothermal therapy, photodynamic therapy, gene therapy, immunotherapy, ferroptosis therapy, sonodynamic therapy, chemodynamic therapy, and combination therapy) in treating glioma are summarized. In addition, this review provides some perspectives on the clinical applications of nanomedicines.

(1) Background: Glioblastoma (GBM) is categorized as a grade IV astrocytoma by the World Health Organization (WHO), representing the most aggressive and prevalent form of glioma. It presents a significant clinical challenge, with limited treatment options and poor prognosis. This systematic review evaluates the efficacy and safety of various nanotherapy approaches for GBM and explores future directions in tumor management. Nanomedicine, which involves nanoparticles in the 1–100 nm range, shows promise in improving drug delivery and targeting tumor cells. (2) Methods: Following PRISMA guidelines, a systematic search of databases including Google Scholar, NCBI PubMed, Cochrane Library, and ClinicalTrials.gov was conducted to identify clinical trials on GBM and nanomedicine. The primary outcome measures were median overall survival, progression-free survival, and quality of life assessed through Karnofsky performance scores. The safety profile was assessed by adverse events. (3) Results: The analysis included 225 GBM patients, divided into primary and recurrent sub-populations. Primary GBM patients had a median overall survival of 6.75 months, while recurrent GBM patients had a median overall survival of 9.7 months. The mean PFS period was 2.3 months and 3.92 months in primary GBM and recurrent GBM patients, respectively. Nanotherapy showed an improvement in quality of life, with KPS scores increasing after treatment in recurrent GBM patients. Adverse events were observed in 14.2% of patients. Notably, Bevacizumab therapy exhibited better survival outcomes but with a higher incidence of adverse events. (4) Conclusions: Nanotherapy offers a modest increase in survival with fewer severe side effects. It shows promise in improving the quality of life, especially in recurrent GBM patients. However, it falls short in terms of overall survival compared to Bevacizumab. The heterogeneous nature of treatment protocols and reporting methods highlights the need for standardized multicenter trials to further evaluate the potential of nanomedicine in GBM management.

Natural products have been used in medicine for many years. Many top-selling pharmaceuticals are natural compounds or their derivatives. These plant- or microorganism-derived compounds have shown potential as therapeutic agents against cancer, microbial infection, inflammation, and other disease conditions. However, their success in clinical trials has been less impressive, partly due to the compounds’ low bioavailability. The incorporation of nanoparticles into a delivery system for natural products would be a major advance in the efforts to increase their therapeutic effects. Recently, advances have been made showing that nanoparticles can significantly increase the bioavailability of natural products both in vitro and in vivo. Nanotechnology has demonstrated its capability to manipulate particles in order to target specific areas of the body and control the release of drugs. Although there are many benefits to applying nanotechnology for better delivery of natural products, it is not without issues. Drug targeting remains a challenge and potential nanoparticle toxicity needs to be further investigated, especially if these systems are to be used to treat chronic human diseases. This review aims to summarize recent progress in several key areas relevant to natural products in nanoparticle delivery systems for biomedical applications.

Glioblastoma multiforme (GBM) is the most aggressive and lethal type of brain tumor. Both therapeutic resistance and restricted permeation of drugs across the blood–brain barrier (BBB) play a major role in the poor prognosis of GBM patients. Accumulated evidence suggests that in many human cancers, including GBM, therapeutic resistance can be attributed to a small fraction of cancer cells known as cancer stem cells (CSCs). CSCs have been shown to have stem cell-like properties that enable them to evade traditional cytotoxic therapies, and so new CSC-directed anti-cancer therapies are needed. Nanoparticles have been designed to selectively deliver payloads to relevant target cells in the body, and there is considerable interest in the use of nanoparticles for CSC-directed anti-cancer therapies. Recent advances in the field of nanomedicine offer new possibilities for overcoming CSC-mediated therapeutic resistance and thus significantly improving management of GBM. In this review, we will examine the current nanomedicine approaches for targeting CSCs and their therapeutic implications. The inhibitory effect of various nanoparticle-based drug delivery system towards CSCs in GBM tumors is the primary focus of this review.

Malignant brain tumors are a highly complex and heterogeneous group of neoplasms, with glioblastoma being the most aggressive and treatment-resistant form. Standard therapies remain insufficient, largely due to poor drug penetration across the blood-brain barrier and tumor heterogeneity. Lipid-based nanoemulsions have emerged as promising nanocarriers capable of enhancing drug solubility, protecting unstable compounds, and facilitating targeted delivery across the blood-brain barrier. This scoping review analyzed 19 studies focused on lipid-based nanoemulsions for brain tumor therapy, particularly those incorporating synthetic drugs, natural compounds, and nucleic acids. Key formulation strategies, preparation methods, and physicochemical characteristics were outlined. The majority of studies demonstrated in vitro cytotoxicity against rat C6 and human U87MG glioma cell lines. Particularly, nanoemulsions loaded with temozolomide, and siRNA targeting CD73 reduced tumor growth in glioma-bearing rats, especially via nasal administration. Natural products such as kaempferol and honokiol also showed antiglioma effects in vitro when delivered through nanoemulsions. These findings highlight the potential of nanoemulsions in neuro-oncology, particularly for noninvasive nose-to-brain delivery and gene silencing therapies. Further research is needed to standardize formulations and validate their efficacy and safety in clinical settings.

Central nervous system disorders drive disability, yet many neuroactive candidates fail because the brain is a hard compartment to dose. Plant derived molecules spanning polyphenols, alkaloids, terpenoids, and cannabinoids are attractive because their pleiotropic actions can engage oxidative stress, neuroinflammation, and circuit dysfunction. In practice, the blood-brain barrier (BBB) restricts most native phytochemicals through tight-junction selectivity, rapid metabolism, low solubility, and transporter-mediated efflux. Key gaps include poor standardization of exposure metrics, limited human relevant BBB models, and few head-to-head studies that compare delivery platforms on the same payload and outcome. This review tackles the mismatch between mechanistic promise and reliable brain exposure that stalls translation. The objectives are to link phytochemical liabilities to enabling strategies in nanomedicine, alternative routes, and transporter-targeted prodrugs, and to propose decision-grade endpoints for translation. We synthesize evidence on BBB transport logic, nanocarrier families, targeting ligands, intranasal delivery, focused ultrasound mediated opening, and prodrug approaches that hijack influx transporters, while foregrounding safety and chemistry, manufacturing, and controls (CMC) constraints. Here we highlight that effective neurotherapeutics emerge when chemistry, carrier, route, and measurement are co designed rather than optimized in isolation. This framework can guide platform selection, de-risk first in-human studies, and sharpen trial endpoints. More broadly, it offers a transferable playbook for barrier-limited drug development across neurology, psychiatry, and oncology.

Inhibition of tumor growth and normalization of immune responses in the tumor microenvironment (TME) are critical issues for improving cancer therapy. However, in the treatment of glioma, effective nanomedicine has limited access to the brain because of the blood–brain barrier (BBB). Previously, we demonstrated nano-sized ginseng-derived exosome-like nanoparticles (GENs) consisting of phospholipids including various bioactive components, and evaluated anti-tumor immune responses in T cells and Tregs to inhibit tumor progression. It was found that the enhanced targeting ability of GENs to the BBB and glioma induced a significant therapeutic effect and exhibited strong efficacy in recruiting M1 macrophage expression in the TME. GENs were demonstrated to be successful candidates in glioma therapeutics both in vitro and in vivo, suggesting excellent potential for inhibiting glioma progression and regulating tumor-associated macrophages (TAMs).

Efficient drug delivery methods are crucial in modern pharmacotherapy to enhance treatment efficacy, minimize adverse effects, and improve patient compliance. Particularly in the context of glioblastoma treatment, there has been a recent surge in interest in using natural dietary components as innovative carriers for drug delivery. These food-derived carriers, known for their safety, biocompatibility, and multifunctional properties, offer significant potential in overcoming the limitations of conventional drug delivery systems. This article thoroughly overviews numerous natural dietary components, such as polysaccharides, proteins, and lipids, used as drug carriers. Their mechanisms of action, applications in different drug delivery systems, and specific benefits in targeting glioblastoma are examined. Additionally, the safety, biocompatibility, and regulatory considerations of employing food components in drug formulations are discussed, highlighting their viability and future prospects in the pharmaceutical field.

BACKGROUND Several natural compounds have demonstrated potential for the treatment of central nervous system disorders such as ischemic cerebrovascular disease, glioblastoma, neuropathic pain, neurodegenerative diseases, multiple sclerosis and migraine. This is due to their well-known antioxidant, anti-inflammatory, neuroprotective, anti-tumor, anti-ischemic and analgesic properties. Nevertheless, many of these molecules have poor aqueous solubility, low bioavailability and extensive gastrointestinal and/or hepatic first-pass metabolism, leading to a quick elimination as well as low serum and tissue concentrations. Thus, the intranasal route emerged as a viable alternative to oral or parenteral administration, by enabling a direct transport into the brain through the olfactory and trigeminal nerves. With this approach, the blood-brain barrier is circumvented and peripheral exposure is reduced, thereby minimizing possible adverse effects. OBJECTIVE Herein, brain-targeting strategies for the nose-to-brain delivery of natural compounds, including flavonoids, cannabinoids, essential oils and terpenes, will be reviewed and discussed. Brain and plasma pharmacokinetics of these molecules will be analyzed and related to their physicochemical characteristics and formulation properties. CONCLUSION Natural compounds constitute relevant alternatives for the treatment of brain diseases but often require loading into nanocarrier systems to reach the central nervous system in sufficient concentrations. Future challenges lie in a deeper characterization of their therapeutic mechanisms and in the development of effective, safe and brain-targeted delivery systems for their intranasal administration.

Glioma is the leading cancer of the central nervous system (CNS). The efficacy of glioma treatment is significantly hindered by the presence of the blood-brain barrier (BBB) and blood-brain tumour barrier (BBTB), which prevent most drugs from entering the brain and tumours. Hence, we established a novel drug delivery nanosystem of brain tumour-targeting that could self-assemble the method using an amphiphilic Zein protein isolated from corn. Zein's amphiphilicity prompted it to self-assembled into NPs, efficiently containing TMZ. This allowed us to investigate temozolomide (TMZ) for glioblastoma (GBM) treatment. To construct TMZ-encapsulated NPs (TMZ@RVG-Zein NPs), the NPs' Zein was clocked to rabies virus glycoprotein 29 (RVG29). To verify that the NPs could penetrate the BBB and precisely target and kill the GBM cancer cell line, in vitro studies were performed. The process of NPs penetrating cancer cell membranes was investigated using enzyme-linked immunosorbent assays (ELISAs) to measure the expressions of nicotinic acetylcholine receptors (nAChRs) on the U87 cell line. Therefore, effective targeted brain cancer treatment is possible by forming NP clocks, a cell-penetrating natural Zein protein with an RVG29. These NPs can penetrate the blood-brain barrier (BBB) and enter the glioblastoma (U87) cell line to release TMZ. These NPs have a distinct cocktail of biocompatibility and brain-targeting abilities, making them ideal for involving brain diseases.

Background A major challenge in central nervous system disorders such glioblastoma includes the presence of a blood-brain barrier which restricts the delivery of therapeutic agents to the brain, thereby limiting the effectiveness of most conventional treatments. Moreover, the discovery of novel drugs for glioblastoma has been limited hence drug repurposing has gained traction leveraging existing drugs like itraconazole. Plant-derived extracellular vesicles (PDEVs) have potential as a natural pharmaceutical delivery system owing to their therapeutic capabilities. These PDEVs may be a good candidate for blood-brain barrier permeation due to their biomolecular composition and high drug loading efficiency of itraconazole. In this work, PDEVs isolated from aloe aborescens (aloe), Zingiber officinale (ginger) and Nigella sativa seeds [black cumin seeds (BCS)] were compared in terms of their physicochemical properties, drug release kinetics, cytotoxicity, cellular uptake in glioblastoma cells and BBB permeability. Results All PDEVs displayed nanoscale sizes ranging from 103.5 to 141 nm with negative surface charge and a spherical morphological shape observed via SEM. The drug release kinetics was assessed using different mathematical models depicting the PDEVs prolonged drug release with < 50% releasing over 21 days. The cytotoxicity studies showed that the PDEVs resulted in a higher cell viability in the non-cancerous cell line compared to A172 glioblastoma cell line. The cellular internalization of the drug showed poor uptake of blank PDEVs compared to loaded PDEVs in glioblastoma cells. The BBB permeability test showed that ginger and aloe EVs permeated the BBB whilst BCS blank and loaded EVs did not permeate the BBB. Conclusions This delivery system improves the ability of plant-derived extracellular vesicles to cross the blood-brain barrier, addressing a key challenge in delivering treatments to the brain. Through successful encapsulation of itraconazole, it paves the way for glioblastoma treatment by repurposing itraconazole with improved efficacy and reduced side effects. Furthermore, this can be incorporated in various drug delivery vehicles depending on the route of administration and therapeutic outcome i.e. intranasal, intravenous, or oral route. Future studies focus on determining the composition of PDEVs to enable engineering strategies for next generation targeting via surface modification.

Recent studies have highlighted the promising chemotherapeutic and antioxidant properties of phytochemicals, which offer the advantage of fewer side effects compared to conventional therapies. Glioblastoma multiforme (GBM) is an aggressive and fatal brain tumor with a poor prognosis and limited treatment options. Despite advances in surgery, radiotherapy, and chemotherapy, effective GBM treatments remain a major challenge, largely due to the restrictive nature of the blood–brain barrier and the severe side effects associated with conventional drugs. The integration of herbal-based compounds into nanocarrier-based multimodal drug delivery systems holds significant potential to enhance therapeutic efficacy and overcome current limitations. This review begins with an overview of GBM, including current treatment strategies and the challenges associated with drug delivery to the brain. We then explore various phytochemicals and medicinal plants used in GBM therapy and their incorporation into nanostructured delivery systems. Finally, we discuss ongoing clinical trials and the biological fate of nanostructures, emphasizing their potential in GBM treatment. The therapeutic efficacy of natural compounds can be markedly improved through nanocarrier-based delivery. There is a growing need for novel natural biomaterials and their combination with potent chemotherapeutics, given their desirable characteristics such as biodegradability, biocompatibility, accessibility, renewability, and low toxicity. Recent advancements underscore the potential of combining nanotechnology with phytotherapy as a promising approach for GBM treatment—an area where conventional therapies have often proven inadequate.

Glioblastoma (GBM), a highly malignant central nervous system tumor, poses a major therapeutic challenge due to the poor blood-brain barrier (BBB) permeability and an immunosuppressive tumor microenvironment. Notably, silymarin, a natural compound known for its anti-inflammatory and liver-protective properties, has emerged as a promising candidate for GBM immunotherapy through the inhibition of glycolysis and induction of mitochondrial damage. In this study, we developed a silymarin-repurposed, site-specific delivery photo-chemotherapy nanoplatform, designed to synergistically suppress mitochondria for efficient GBM immunotherapy. The platform utilizes a self-assembly strategy incorporating brain-targeted lactoferrin (LF), triphenylphosphine-modified chlorin e6 (TCe6), and silymarin. Mechanistically, LF facilitates targeted binding to low-density lipoprotein receptor-related protein-1 (LRP1), enabling BBB penetration and inducing mitochondrial dysfunction in GBM cells through TCe6-mediated intracellular reactive oxygen species (ROS) generation and silymarin-induced glycolysis suppression. This mitochondrial dysfunction triggers the activation of the AMPK pathway, leading to the degradation of programmed cell death ligand-1 (PD-L1) and the activation of the cGAS-STING pathway, thereby enhancing the anti-tumor immune response. As anticipated, this nanoplatform significantly improves BBB permeability and antitumour immunity, providing an innovative drug repurposing strategy for effective GBM immunotherapy.

Tailored nanocarriers and bioconjugates for combating glioblastoma and other brain tumors Fatema ELAmrawy1, Amr A. Othman1, Chris Adkins2, Aliaa Helmy1, Mohamed I. Nounou1,3 1Department of Pharmaceutics and Pharmaceutical Sciences, Faculty of Pharmacy, Alexandria University, Alexandria 21521, Egypt. 2Department of Basic Pharmaceutical Sciences, Health Sciences Center, School of Pharmacy, West Virginia University, Morgantown, WV 26506, USA. 3Department of Pharmaceutical Sciences, Appalachian College of Pharmacy, Oakwood, VA 24631, USA. Correspondence to: Dr. Mohamed I. Nounou, Department of Pharmaceutical Sciences, Appalachian College of Pharmacy, Oakwood, VA 24631, USA. E-mail: nounou@acp.edu Worldwide, the incidence of primary brain tumors is on the rise. Unfortunately, noninvasive drug therapy is hampered by poor access of most drugs to the brain due to the insurmountable blood-brain barrier (BBB). Nanotechnology holds great promise for noninvasive therapy of severe brain diseases. Furthermore, recent bioconjugation strategies have enabled the invasion of the BBB via tailored-designed bioconjugates either with targeting moieties or alterations in the physicochemical and/or the pharmacokinetic parameters of central nervous system (CNS) active pharmaceutical ingredients. Multifunctional systems and new entities are being developed to target brain cells and tumor cells to resist the progression of brain tumors. Direct conjugation of an FDA-approved drug with a targeting moiety, diagnostic moiety, or pharmacokinetic-modifying moiety represents another current approach in combating brain tumors and metastases. Finally, genetic engineering, stem cells, and vaccinations are innovative nontraditional approaches described in different patents for the management of brain tumors and metastases. This review summarizes the recent technologies and patent applications in the past five years for the noninvasive treatment of glioblastoma and other brain tumors. Till now, there has been no optimal strategy to deliver therapeutic agents to the CNS for the treatment of brain tumors and metastases. Intensive research efforts are ongoing to bring novel CNS delivery systems to potential clinical application.

Glioblastoma (GBM) poses a formidable challenge because of its high morbidity and mortality. The therapeutic efficacy of GBM is significantly hampered by the intricate blood-brain barrier (BBB) and blood-brain tumor barrier (BBTB). Nanomaterial-based brain-targeted delivery systems have shown great potential for effectively delivering therapeutic agents for GBM treatment by overcoming the limitations of conventional drugs, such as poor BBB penetration, a short half-life, and low bioavailability. This review focuses on an in-depth analysis of the interplay between the BBB/BBTB and drug transport kinetics while analyzing innovative nanoparticle-mediated strategies for enhanced GBM treatment. Moreover, the delivery strategies of nanoparticle-based brain-targeted systems are emphasized, with particular attention given to biomimetic nanoparticles (BMNPs), whose unique advantages. The current challenges, translational potential, and future research directions in this rapidly evolving field are comprehensively discussed, highlighting advances in nanomaterial applications. This review aims to stimulate further research into GBM delivery systems, offering promising avenues for maximizing the therapeutic effects of gene drugs or chemotherapeutic agents in practical applications.

Glioblastoma multiforme (GBM) has been considered to be the most malignant brain tumors. Due to the existence of various barriers including the blood–brain barrier (BBB) and blood–brain tumor barrier (BBTB) greatly hinder the accumulation and deep penetration of chemotherapeutics, the treatment of glioma remains to be the most challenging task in clinic. In order to circumvent these hurdles, we developed a multifunctional liposomal glioma-targeted drug delivery system (c(RGDyK)/pHA-LS) modified with cyclic RGD (c(RGDyK)) and p-hydroxybenzoic acid (pHA) in which c(RGDyK) could target integrin αvβ3 overexpressed on the BBTB and glioma cells and pHA could target dopamine receptors on the BBB. In vitro, c(RGDyK)/pHA-LS could target glioblastoma cells (U87), brain capillary endothelial cells (bEnd.3) and umbilical vein endothelial cells (HUVECs) through a comprehensive pathway. Besides, c(RGDyK)/pHA-LS could also increase the cytotoxicity of doxorubicin encapsulated in liposomes on glioblastoma cells, and was able to penetrate inside the glioma spheroids after traversing the in vitro BBB and BBTB. In vivo, we demonstrated the targeting ability of c(RGDyK)/pHA-LS to intracranial glioma. As expected, c(RGDyK)/pHA-LS/DOX showed a median survival time of 35 days, which was 2.31-, 1.76- and 1.5-fold higher than that of LS/DOX, c(RGDyK)-LS/DOX, and pHA-LS/DOX, respectively. The findings here suggested that the multifunctional glioma-targeted drug delivery system modified with both c(RGDyK) and pHA displayed strong antiglioma efficiency in vitro and in vivo, representing a promising platform for glioma therapy.

Despite the application of aggressive surgery, radiotherapy and chemotherapy in clinics, brain tumors are still a difficult health challenge due to their fast development and poor prognosis. Brain tumor-targeted drug delivery systems, which increase drug accumulation in the tumor region and reduce toxicity in normal brain and peripheral tissue, are a promising new approach to brain tumor treatments. Since brain tumors exhibit many distinctive characteristics relative to tumors growing in peripheral tissues, potential targets based on continuously changing vascular characteristics and the microenvironment can be utilized to facilitate effective brain tumor-targeted drug delivery. In this review, we briefly describe the physiological characteristics of brain tumors, including blood–brain/brain tumor barriers, the tumor microenvironment, and tumor stem cells. We also review targeted delivery strategies and introduce a systematic targeted drug delivery strategy to overcome the challenges.

Abstract Therapeutic outcome for the treatment of glioma was often limited due to the two barriers involved: the blood-brain barrier (BBB) and blood-brain tumor barrier (BBTB). Therefore, the development of nanocarriers that possess both BBB and BBTB permeability and glioma-targeting ability is of great importance for the chemotherapy of glioma. New frontiers in nanomedicine are advancing the research of new biomaterials. Here we constructed a natural high-density lipoprotein particle (HDL)-based drug delivery system with the dual-modification of T7 and dA7R peptide ligand (T7/dA7R-HDL) to achieve the above goals. HDL, the smallest lipoprotein, plays a biological role and is highly suitable as a platform for delivering imaging and therapeutic agents. T7 is a seven-peptide ligand of transferrin receptors (TfR) capable of circumventing the BBB and then targeting glioma. dA7R is a d-peptide ligand of vascular endothelial growth factor receptor 2 (VEGFR 2) overexpressed on angiogenesis, presenting excellent glioma-homing property. 10-Hydroxycamptothecin (HCPT), a hydrophobic anti-cancer drug, was used as the model drug in this study. By combining the dual-targeting delivery effect, the dual-modified HDL displayed higher glioma localization than that of single ligand-modified HDL or free HCPT. After loading with HCPT, T7/dA7R-HDL showed the most favorable anti-glioma effect in vivo. These results demonstrated that the dual-targeting natural nanocarriers strategy provides a potential method for improving brain drug delivery and anti-glioma treatment efficacy.

Tumor-associated macrophages (TAMs) are closely related to the progression of glioblastoma multiform (GBM) and its development of therapeutic resistance to conventional chemotherapy. TAM-targeted therapy combined with conventional chemotherapy has emerged as a promising strategy to combat GBM. However, the presence of the blood-brain barrier (BBB) severely limits the therapeutic efficacy. Meanwhile, the lack of ability to distinguish different targeted cells also poses a challenge for precise therapy. Herein, we propose a cathepsin B (CTSB)-responsive programmed brain-targeted delivery system (D&R-HM-MCA) for simultaneous TAM-targeted and GBM-targeted delivery. D&R-HM-MCA could cross the BBB via low density lipoprotein receptor-associated protein 1 (LRP1)-mediated transcytosis. Upon reaching the GBM site, the outer angiopep-2 modification could be detached from D&R-HM-MCA via cleavage of the CTSB-responsive peptide, which could circumvent abluminal LRP1-mediated efflux. The exposed p-aminophenyl-α-d-mannopyranoside (MAN) modification could further recognize glucose transporter-1 (GLUT1) on GBM and macrophage mannose receptor (MMR) on TAMs. D&R-HM-MCA could achieve chemotherapeutic killing of GBM and simultaneously induce TAM polarization from anti-inflammatory M2 phenotype to pro-inflammatory M1 phenotype, thus resensitizing the chemotherapeutic response and improving anti-GBM immune response. This CTSB-responsive brain-targeted delivery system not only can improve brain delivery efficiency, but also can enable the combination of chemo-immunotherapy against GBM. The effectiveness of this strategy may provide thinking for designing more functional brain-targeted delivery systems and more effective therapeutic regimens.

Nanotechnology has accelerated an exponentially growing interest in novel drug delivery and healthcare systems. Nanotechnology is an efficient approach that can conquer a multitude …

BackgroundEffective transvascular delivery of nanoparticle-based chemotherapeutics across the blood-brain tumor barrier of malignant gliomas remains a challenge. This is due to our limited understanding of nanoparticle properties in relation to the physiologic size of pores within the blood-brain tumor barrier. Polyamidoamine dendrimers are particularly small multigenerational nanoparticles with uniform sizes within each generation. Dendrimer sizes increase by only 1 to 2 nm with each successive generation. Using functionalized polyamidoamine dendrimer generations 1 through 8, we investigated how nanoparticle size influences particle accumulation within malignant glioma cells.MethodsMagnetic resonance and fluorescence imaging probes were conjugated to the dendrimer terminal amines. Functionalized dendrimers were administered intravenously to rodents with orthotopically grown malignant gliomas. Transvascular transport and accumulation of the nanoparticles in brain tumor tissue was measured in vivo with dynamic contrast-enhanced magnetic resonance imaging. Localization of the nanoparticles within glioma cells was confirmed ex vivo with fluorescence imaging.ResultsWe found that the intravenously administered functionalized dendrimers less than approximately 11.7 to 11.9 nm in diameter were able to traverse pores of the blood-brain tumor barrier of RG-2 malignant gliomas, while larger ones could not. Of the permeable functionalized dendrimer generations, those that possessed long blood half-lives could accumulate within glioma cells.ConclusionThe therapeutically relevant upper limit of blood-brain tumor barrier pore size is approximately 11.7 to 11.9 nm. Therefore, effective transvascular drug delivery into malignant glioma cells can be accomplished by using nanoparticles that are smaller than 11.7 to 11.9 nm in diameter and possess long blood half-lives.

The blood-brain barrier represents a significant challenge for the treatment of high-grade gliomas, and our understanding of drug transport across this critical biointerface remains limited. To advance preclinical therapeutic development for gliomas, there is an urgent need for predictive in vitro models with realistic blood-brain barrier vasculature. Here, we report a vascularized human glioblastoma (GBM) model in a microfluidic device that accurately recapitulates brain tumor vasculature with self-assembled endothelial cells, astrocytes, and pericytes to investigate the transport of targeted nanotherapeutics across the blood-brain barrier and into GBM cells. Using modular layer-by-layer assembly, we functionalized the surface of nanoparticles with GBM-targeting motifs to improve trafficking to tumors. We directly compared nanoparticle transport in our in vitro platform with transport across mouse brain capillaries using intravital imaging, validating the ability of the platform to model in vivo blood-brain barrier transport. We investigated the therapeutic potential of functionalized nanoparticles by encapsulating cisplatin and showed improved efficacy of these GBM-targeted nanoparticles both in vitro and in an in vivo orthotopic xenograft model. Our vascularized GBM model represents a significant biomaterials advance, enabling in-depth investigation of brain tumor vasculature and accelerating the development of targeted nanotherapeutics. Significance Statement The blood-brain barrier represents a major therapeutic challenge for the treatment of glioblastoma, and there is an unmet need for in vitro models that recapitulate human biology and are predictive of in vivo response. Here we present a new microfluidic model of vascularized glioblastoma featuring a tumor spheroid in direct contact with self-assembled vascular networks comprised of human endothelial cells, astrocytes, and pericytes. This model was designed to accelerate the development of targeted nanotherapeutics, and enabled rigorous assessment of a panel of surface-functionalized nanoparticles designed to exploit a receptor overexpressed in tumor-associated vasculature. Trafficking and efficacy data in the in vitro model compared favorably to parallel in vivo data, highlighting the utility of the vascularized glioblastoma model for therapeutic development.

… The intravenously administered biodegradable polymeric nanoparticles loaded with … of experimental glioblastoma. These data, together with the possibility to employ nanoparticles for …

Glioma is the most common tumor of the central nervous system (CNS), with a 5-year survival rate of <35%. Drug therapy, such as chemotherapeutic and immunotherapeutic agents, remains one of the main treatment modalities for glioma, including temozolomide, doxorubicin, bortezomib, cabazitaxel, dihydroartemisinin, immune checkpoint inhibitors, as well as other approaches such as siRNA, ferroptosis induction, etc. However, the filter function of the blood-brain barrier (BBB) reduces the amount of drugs needed to effectively target CNS tumors, making it one of the main reasons for poor drug efficacies in glioma. Thus, finding a suitable drug delivery platform that can cross the BBB, increase drug aggregation and retainment in tumoral areas and avoid accumulation in non-targeted areas remains an unsolved challenge in glioma drug therapy. An ideal drug delivery system for glioma therapy should have the following features: (1) prolonged drug life in circulation and effective penetration through the BBB; (2) adequate accumulation within the tumor (3) controlled-drug release modulation; (4) good clearance from the body without significant toxicity and immunogenicity, etc. In this regard, due to their unique structural features, nanocarriers can effectively span the BBB and target glioma cells through surface functionalization, providing a new and effective strategy for drug delivery. In this article, we discuss the characteristics and pathways of different nanocarriers for crossing the BBB and targeting glioma by listing different materials for drug delivery platforms, including lipid materials, polymers, nanocrystals, inorganic nanomaterials, etc.

Glioblastoma (GBM) is a devastating primary brain tumor resistant to conventional therapies. A major obstacle to GBM treatment is the blood-brain barrier (BBB), or blood-glioma barrier, which prevents the transport of systemically administered (chemotherapeutic) drugs into the tumor. This study reports the design of dodecamer peptide (G23)-functionalized polydopamine (pD)-coated curcumin-loaded zein nanoparticles (CUR-ZpD-G23 NPs) that efficiently traversed the BBB, and delivered curcumin to glioblastoma cells. The NPs enhanced the cellular uptake of curcumin by C6 glioma cells compared to free curcumin, and showed high penetration into 3D tumor spheroids. Functionalization of the NPs with G23 stimulated BBB crossing and tumor spheroid penetration. Moreover, the NPs markedly inhibited proliferation and migration and induced cell death in liquid and soft agar models of C6 glioma cell growth. Fluorescence microscopy and flow cytometry studies showed that the CUR-ZpD-G23 NPs increased cellular ROS production and induced apoptosis of C6 glioma cells. Following in vivo intravenous injection in zebrafish, ZpD-G23 NPs demonstrated the ability to circulate, which is a first prerequisite for their use in targeted drug delivery. In conclusion, zein-polydopamine-G23 NPs show potential as a drug delivery platform for therapy of GBM, which requires further validation in in vivo glioblastoma models.

Glioblastoma is one of the most aggressive central nervous system malignancies with high morbidity and mortality. Current clinical approaches, including surgical resection, radiotherapy, and chemotherapy, are limited by the difficulty of targeting brain lesions accurately, leading to disease recurrence and fatal outcomes. The lack of effective treatments has prompted researchers to continuously explore novel therapeutic strategies. In recent years, nanomedicine has made remarkable progress and expanded its application in brain drug delivery, providing a new treatment for brain tumors. Against this background, this article reviews the application and progress of nanomedicine delivery systems in brain tumors. In this paper, the mechanism of nanomaterials crossing the blood-brain barrier is summarized. Furthermore, the specific application of nanotechnology in glioblastoma is discussed in depth.

The blood-brain barrier (BBB) constitutes a microvascular network responsible for excluding most drugs from the brain. Treatment of brain tumors is limited by the impermeability of the BBB and, consequently, survival outcomes for malignant brain tumors remain poor. Nanoparticles (NPs) represent a potential solution to improve drug transport to brain tumors, given their small size and capacity to target tumor cells. Here, we review the unique physical and chemical properties of NPs that aid in BBB transport and discuss mechanisms of NP transport across the BBB, including paracellular transport, carrier-mediated transport, and adsorptive- and receptor-mediated transcytosis. The major types of NPs investigated for treatment of brain tumors are detailed, including polymeric NPs, liposomes, solid lipid NPs, dendrimers, metals, quantum dots, and nanogels. In addition to their role in drug delivery, NPs can be used as imaging contrast agents and can be conjugated with imaging probes to assist in visualizing tumors, demarcating lesion boundaries and margins, and monitoring drug delivery and treatment response. Multifunctional NPs can be designed that are capable of targeting tumors for both imaging and therapeutic purposes. Finally, limitations of NPs for brain tumor treatment are discussed.

The blood–brain barrier (BBB) can block drug delivery into the human brain, and thus remains the primary obstacle in the efficient treatment of glioma. Herein, Polyporus Amboinensis Lam (PAL)‐functionalized selenium nanoparticles (SeNPs) (hereafter referred to as PAL‐SeNPs) are fabricated as a cancer‐targeted nanosystem to antagonize the BBB and thus enhance anti‐glioma ability. The robust synthesis of PAL‐SeNPs confers the nanosystem with high‐stability and the ideal size for efficient endocytosis in glioma cells. The structure similarity of PAL with αvβ3 integrin, which is overexpressed on glioma cells, increases the selectivity between glioma cells and normal gliocytes via the PAL/αvβ3 integrin‐mediated targeting effect, and displays a favorable anti‐glioma effect by hastening m‐TOR‐mediated cell apoptosis. Pharmacokinetics analysis demonstrates that PAL‐SeNPs improves the half‐life of SeNPs in blood and ensures their sufficient accumulation in the brain. PAL‐SeNPs facilitate effective transportability across the BBB and exhibit superior permeability into glioma tumor spheroid. Taken together, this study provides a robust strategy of using SeNPs to overcome the BBB for enhanced anti‐glioma treatment.

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Abstract The blood-brain barrier (BBB) and blood-tumor barrier (BTB) pose substantial challenges to efficacious drug delivery for glioblastoma multiforme (GBM), a primary brain tumor with poor prognosis. Nanoparticle-based combinational strategies have emerged as promising modalities to overcome these barriers and enhance drug penetration into the brain parenchyma. This review discusses various nanoparticle-based combinatorial approaches that combine nanoparticles with cell-based drug delivery, viral drug delivery, focused ultrasound, magnetic field, and intranasal drug delivery to enhance drug permeability across the BBB and BTB. Cell-based drug delivery involves using engineered cells as carriers for nanoparticles, taking advantage of their intrinsic migratory and homing capabilities to facilitate the transport of therapeutic payloads across BBB and BTB. Viral drug delivery uses engineered viral vectors to deliver therapeutic genes or payloads to specific cells within the GBM microenvironment. Focused ultrasound, coupled with microbubbles or nanoparticles, can temporarily disrupt the BBB to increase drug permeability. Magnetic field-guided drug delivery exploits magnetic nanoparticles to facilitate targeted drug delivery under an external magnetic field. Intranasal drug delivery offers a minimally invasive avenue to bypass the BBB and deliver therapeutic agents directly to the brain via olfactory and trigeminal pathways. By combining these strategies, synergistic effects can enhance drug delivery efficiency, improve therapeutic efficacy, and reduce off-target effects. Future research should focus on optimizing nanoparticle design, exploring new combination strategies, and advancing preclinical and clinical investigations to promote the translation of nanoparticle-based combination therapies for GBM.

… nanoparticles with specific ligands, such as peptides and antibodies, that can specifically bind to receptors/transporters expressed on both blood-brain barrier and glioma … the transport …

Abstract Glioblastoma is the most aggressive and lethal primary brain tumor in adults, with current treatment options offering only limited improvement in patient survival. Despite the advancement of modalities such as immunotherapy, targeted therapy, gene therapy, focused ultrasound, and tumor-treating fields, therapeutic efficacy remains unsatisfactory due to challenges such as the blood-brain barrier, tumor heterogeneity, and treatment resistance. Nanotechnology has emerged as a promising platform to enhance the delivery, specificity, and combinatorial potential of these therapies. By enabling precise and multifunctional delivery of therapeutic agents, nanoscale systems hold the potential to overcome critical biological and pharmacological barriers in glioblastoma treatment. This review provides an overview of recent progress in nanomedicine-based strategies for glioblastoma, critically examines the key challenges that limit their clinical translation, and highlights innovative approaches designed to improve therapeutic outcomes. Future perspectives on how nanotechnology may reshape the landscape of brain tumor treatment are also discussed.

Abstract Gliomas are the most common tumor of the central nervous system. However, the presence of the brain barrier blocks the effective delivery of drugs and leads to the treatment failure of various drugs. The development of a nanoparticle drug delivery system (NDDS) can solve this problem. In this review, we summarized the brain barrier (including blood–brain barrier (BBB), blood–brain tumor barriers (BBTB), brain–cerebrospinal fluid barrier (BCB), and nose-to-brain barrier), NDDS of glioma (such as passive targeting systems, active targeting systems, and environmental responsive targeting systems), and NDDS efficacy improvement strategies and deficiencies. The research prospect of drug-targeted delivery systems for glioma is also discussed.

Effective treatments for brain tumors remain one of the most urgent and unmet needs in modern oncology. This is due not only to the presence of the neurovascular unit/blood–brain barrier (NVU/BBB) but also to the heterogeneity of barrier alteration in the case of brain tumors, which results in what is referred to as the blood–tumor barrier (BTB). Herein, we discuss this heterogeneity, how it contributes to the failure of novel pharmaceutical treatment strategies, and why a “whole brain” approach to the treatment of brain tumors might be beneficial. We discuss various methods by which these obstacles might be overcome and assess how these strategies are progressing in the clinic. We believe that by approaching brain tumor treatment from this perspective, a new paradigm for drug delivery to brain tumors might be established.

Gliomas constitute about 80% of brain tumors and have a meager two-year survival rate. The treatment options available are very few because of poor prognosis and a lack of targeted nanodelivery systems that can cross the blood-brain barrier (BBB) and the blood-tumor barrier. This short review attempts to clarify the challenges for delivery systems designed to cross the BBB, and provides a brief description of the different types of targeted nanodelivery system that have shown potential for success in delivering drugs to the brain. Further, this review describes the most recent studies that have developed nanoparticles for brain delivery in the past five years. We also provide an insight into the most recent clinical trials designed to assess the efficacy of these nanodelivery systems for glioma.

Abstract Gliomas are the most prevalent Central Nervous System (CNS) tumors. Among them, glioblastoma (grade IV) is the most challenging brain cancer because of its highly aggressive nature, treatment resistance and poor prognosis. Matrix metalloproteinase (MMP) is a family of zinc-dependent protein hydrolases. In recent years, MMPs have become a research focus owing to their central role in tumor microenvironment remodeling, angiogenesis, invasion, metastasis. Clinical studies have shown that the expression levels of MMPs in glioma tissues exhibit a significant positive correlation with the degree of malignancy and aggressiveness of gliomas. Therefore, the idea of MMPs as a detection target and therapeutic target can be proposed. Nanoparticle drug delivery system, as a cutting-edge technology, has shown great potential and broad prospects in clinical applications. The system realizes the targeted delivery, sustained-release control and bioavailability of drugs, and provides new ideas and means for the management of various pathological conditions. In this review, we will comprehensively discuss the expression relationship and major regulatory mechanisms between MMPs and gliomas, the composition of nano-drug delivery systems, routes of administration, and common types of nanomaterials used for the treatment of gliomas. In addition, we focus on cell-penetrating peptides (CPPs) as an entry point. We summarize the common kinds of activatable CPPs and how they are applied in nano-drug delivery systems. It is also found that MMP-responsive systems, which can be used for the treatment of gliomas, can activate CPPs, and through the synergistic effect between CPPs and MMPs, MMPs can be used as detection or therapeutic targets and combined with nano-drug delivery system for the medical management of gliomas. The nano-drug delivery system can demonstrate exceptional blood-brain barrier (BBB) penetration efficiency and precisely target the glioma region to release the drug. This delivery approach may prove to be beneficial for glioma patients.

… a particular emphasis on the rapidly evolving strategy of nanomedicine. By encapsulating … the behavior of nanodelivery systems used in GBM treatment. Heterogeneity manifests not …

Drugs for tumor treatment face various challenges, including poor solubility, poor stability, short blood half-life, nontargeting ability, and strong toxic side effects. Fortunately, nanodrug delivery systems provide excellent solution to these problems. However, nanodrugs for glioma treatment also face some key challenges including overcoming the blood–brain barrier (BBB) and, specifically, accumulation in glioma lesions. In this review, we systematically summarize the advantages and disadvantages of combined strategies for nanodrugs noninvasively overcoming BBB and actively targeting glioma lesions to achieve effective glioma therapy. Common noninvasive strategies for nanodrugs overcoming the BBB include bypassing the BBB via the nose-to-brain route, opening the tight junction of the BBB by focused ultrasound with microbubbles, and transendothelial cell transport by intact cell loading, ligand decoration, or cell membrane camouflage of nanodrugs. Actively targeting glioma lesions after overcoming the BBB is another key factor helping nanodrugs accurately treat in situ gliomas. This aim can also be achieved by loading nanodrugs into intact cells and modifying ligand or cell membrane fragments on the surface of nanodrugs. Targeting decorated nanodrugs can guarantee precise glioma killing and avoid side effects on normal brain tissues that contribute to the specific recognition of glioma lesions. Furthermore, the challenges and prospects of nanodrugs in clinical glioma treatment are discussed.

The greatest obstacle to using drugs to treat brain tumors is the blood-brain barrier (BBB), making it difficult for conventional drug molecules to enter the brain. Therefore, how to safely and effectively penetrate the BBB to achieve targeted drug delivery to brain tumors has been a challenging research problem. With the intensive research in micro- and nanotechnology in recent years, nano drug-targeted delivery technologies have shown great potential to overcome this challenge, such as inorganic nanocarriers, organic polymer-carriers, liposomes, and biobased carriers, which can be designed in different sizes, shapes, and surface functional groups to enhance their ability to penetrate the BBB and targeted drug delivery for brain tumors. In this review, the composition and overcoming patterns of the BBB are detailed, and then the hot research topics of drug delivery carriers for brain tumors in recent years are summarized, and their mechanisms of action on the BBB and the factors affecting drug delivery are described in detail, and the effectiveness of targeted therapy for brain tumors is evaluated. Finally, the challenges and dilemmas in developing brain tumor drug delivery systems are discussed, which will be promising in the future for targeted drug delivery to brain tumors based on micro-nanocarriers technology.

Treatment of brain tumors is challenging since the blood–brain tumor barrier prevents chemotherapy drugs from reaching the tumor site in sufficient concentrations. Nanomedicines have great potential for therapy of brain disorders but are still uncommon in clinical use despite decades of research and development. Here, we provide an update on nano-carrier strategies for improving brain drug delivery for treatment of brain tumors, focusing on liposomes, extracellular vesicles and biomimetic strategies as the most clinically feasible strategies. Finally, we describe the obstacles in translation of these technologies including pre-clinical models, analytical methods and regulatory issues.

Abstract Drug delivery systems based on nanoparticles (nano-DDS) have aroused attentions for the treatment of glioblastoma (GBM), the most malignant brain cancer with a dismal prognosis. However, there are still numerous unmet challenges for traditional nano-DDS, such as the poor nanoparticle penetration, short retention in the GBM parenchyma and low glioma targeting ability. Herein, we used Pep-1 and CREKA peptides to construct a novel multifunctional GBM targeting nano-DDS (PC-NP). Pep-1 was used to overcome the blood–brain tumor barrier (BBTB) and home to glioma cells via interleukin-13 receptor-α2-mediated endocytosis, and CREKA was used to bind to fibrin–fibronectin complexes abundantly expressed in tumor microenvironment for enhanced retention in the GBM. Biological studies showed that the cellular uptake of PC-NP by U87MG cells was significantly enhanced compared with the non-targeting NP. Furthermore, CREKA modification increased the binding capacity of PC-NP to fibrin–fibronectin complexes as confirmed by the competition experiment. In accordance with the increased cellular uptake, PC-NP remarkably increased the cytotoxicity of its payload paclitaxel (PTX) against U87MG cells with an IC50 of 0.176 μg/mL. In vivo fluorescence imaging and antiglioma efficacy evaluation further confirmed that PC-NP accumulated effectively and penetrated deeply into GBM tissue. PC-NP-PTX exhibited a median survival time as long as 61 days in intracranial GBM-bearing mice. In conclusion, our findings indicated PC-NP as a promising nano-DDS for GBM targeting delivery of anticancer drugs.

Glioblastoma (GBM) is a highly invasive brain tumor with poor survival outcomes, largely due to incomplete resection, tumor heterogeneity, and the restrictive blood-brain barrier (BBB). Conventional therapies often fail to achieve durable responses, highlighting the immediate need for innovative strategies. Nanotechnology has emerged as a transformative approach, enabling precise imaging, targeted delivery, and multimodal therapy. This review examines diverse nanomaterials, including metallic, metal oxide, carbon-based, polymeric, lipid-based nanoparticles, and exosomes, with a focus on their pharmacological interactions in GBM treatment. Key BBB penetration mechanisms, such as passive diffusion, receptor- and carrier-mediated transcytosis, adsorptivemediated uptake, and cell-mediated transport, are analyzed alongside functionalization strategies (e.g., ligand conjugation, surface charge modification) that enhance tumor selectivity and drug bioavailability. Nanocarrier-drug systems, including liposomes, solid lipid nanoparticles, and exosomebased carriers, have exhibited improved pharmacokinetics, sustained release, and synergistic effects in combination therapies. Metallic and magnetic nanoparticles provide additional advantages in photothermal therapy, radiosensitization, and MRI-guided delivery. Emerging platforms integrate therapeutic and diagnostic functionalities, offering real-time monitoring and controlled release within the tumor microenvironment. Progress in preclinical and early clinical studies emphasizes the potential of biomimetic carriers, stimuli-responsive nanoplatforms, and dual-drug systems to overcome resistance and improve survival. While translational challenges remain, nanotechnologydriven therapeutics represent a promising frontier in the management of GBM, opening new avenues for precise, individualized, and more efficient therapies.

Abstract Glioblastoma (GBM), a highly aggressive form of brain cancer, is considered one of the deadliest cancers, and even with the most advanced medical treatments, most affected patients have a poor prognosis. However, recent advances in nanotechnology offer promising avenues for the development of versatile therapeutic and diagnostic nanoplatforms that can deliver drugs to brain tumor sites through the blood-brain barrier (BBB). Despite these breakthroughs, the use of nanoplatforms in GBM therapy has been a subject of great controversy due to concerns over the biosafety of these nanoplatforms. In recent years, biomimetic nanoplatforms have gained unprecedented attention in the biomedical field. With advantages such as extended circulation times, and improved immune evasion and active targeting compared to conventional nanosystems, bionanoparticles have shown great potential for use in biomedical applications. In this prospective article, we endeavor to comprehensively review the application of bionanomaterials in the treatment of glioma, focusing on the rational design of multifunctional nanoplatforms to facilitate BBB infiltration, promote efficient accumulation in the tumor, enable precise tumor imaging, and achieve remarkable tumor suppression. Furthermore, we discuss the challenges and future trends in this field. Through careful design and optimization of nanoplatforms, researchers are paving the way toward safer and more effective therapies for GBM patients. The development of biomimetic nanoplatform applications for glioma therapy is a promising avenue for precision medicine, which could ultimately improve patient outcomes and quality of life.

This review summarizes articles that have been reported in literature on liposome-based strategies for effective drug delivery across the blood–brain barrier. Due to their unique physicochemical characteristics, liposomes have been widely investigated for their application in drug delivery and in vivo bioimaging for the treatment and/or diagnosis of neurological diseases, such as Alzheimer’s, Parkinson’s, stroke, and glioma. Several strategies have been used to deliver drug and/or imaging agents to the brain. Covalent ligation of such macromolecules as peptides, antibodies, and RNA aptamers is an effective method for receptor-targeting liposomes, which allows their blood–brain barrier penetration and/or the delivery of their therapeutic molecule specifically to the disease site. Additionally, methods have been employed for the development of liposomes that can respond to external stimuli. It can be concluded that the development of liposomes for brain delivery is still in its infancy, although these systems have the potential to revolutionize the ways in which medicine is administered.

… , this review highlights innovative strategies in nanoparticle (NP… limitations in BBB permeability and intratumoral heterogeneity. … focused solely on enhancing BBB penetration and tissue …

… The BBB as a natural barrier regulates the entry of molecules into brain and preserves ionic … of BBB-specific delivery system in up-regulating BBB and BTB permeability and highlight the …

A major obstacle for chemotherapeutics in Glioblastoma (GB) is to reach the tumour cells due to the presence of the blood-brain barrier (BBB) and chemoresistance of anticancer drugs. The present study reports two polyunsaturated fatty acids, gamma-linolenic acid (GLA) and alpha-linolenic acid (ALA) appended nanostructured lipid carriers (NLCs) of a CNS negative chemotherapeutic drug docetaxel (DTX) for targeted delivery to GB. The ligand appended DTX-NLCs demonstrated particle size < 160 nm, PDI < 0.29 and a negative surface charge. The successful linkage of GLA (41 %) and ALA (30 %) ligand conjugation to DTX- NLCs was confirmed by diminished surface amino groups on the NLCs, lower surface charge and FTIR profiling. Fluorophore labelled GLA-DTX-NLCs and ALA-DTX-NLCs permeated the in-vitro 3D BBB model with Papp values of 1.8 × 10-3 and 1.9 × 10-3 cm/s respectively. Following permeation, both formulations showed enhanced uptake by GB immortalised cells while ALA-DTX-NLCs showed higher uptake in patient-derived GB cells as evidenced in an in-vitro 3D blood brain tumour barrier (BBTB) model. Both surface functionalised formulations showed higher internalisation in GB cells as compared to bare DTX-NLCs. ALA-DTX-NLCs and GLA-DTX-NLCs showed 13.9-fold and 6.8-fold higher DTX activity respectively at 24 h as indicated by IC50 values when tested in patient-derived GB cells. ALA-DTX-NLCs displayed better efficacy than GLA-DTX-NLCs when tested against 3D tumour spheroids and patient-derived cells. These novel formulations will contribute widely to overcoming biological barriers for treating glioblastoma.

The effective treatment of glioma through conventional chemotherapy is proved to be a great challenge in clinics. The main reason is due to the existence of two physiological and pathological barriers respectively including the blood-brain barrier (BBB) and blood-brain tumor barrier (BBTB) that prevent most of the chemotherapeutics from efficient delivery to the brain tumors. To address this challenge, an ideal drug delivery system would efficiently traverse the BBB and BBTB and deliver the therapeutics into the glioma cells with high selectivity. Herein, a targeted delivery system was developed based on nanostructured lipid carriers (NLCs) modified with two proteolytically stable D-peptides, D8 and RI-VAP (Dual NLCs). D8 possesses high affinity towards nicotine acetylcholine receptors (nAChRs), overexpressed on brain capillary endothelial cells (BCECs), and can penetrate through BBB with high efficiency. RI-VAP is a specific ligand of cell surface GRP78 (csGRP78), a specific angiogenesis and cancer cell-surface marker, capable of circumventing the BBTB with superior glioma-homing property. Dual NLCs could internalize into BCECs, tumor neovascular endothelial cells, and glioma cells with high specificity and could penetrate through in vitro BBB and BBTB models with excellent efficiency compared to non-targeted or mono-targeted NLCs. In vivo whole-animal imaging and ex vivo imaging further confirmed the superior targeting capability of Dual NLCs towards intracranial glioma. When loaded with Bortezomib (BTZ), Dual NLCs attained the highest therapeutic efficiency by means of in vitro cytotoxicity and apoptosis and prolonged survival rate and anti-glioma behavior in intracranial glioma bearing mice. Collectively, the designed targeting platform in this study could overcome multiple barriers and effectively deliver BTZ to glioma cells, which represent its potential for advanced brain cancer treatment with promising therapeutic outcomes.

Abstract Glioblastoma (GBM) is the most common and lethal primary brain tumor which is highly resistant to conventional radiotherapy and chemotherapy, and cannot be effectively controlled by surgical resection. Due to inevitable recurrence of GBM, it remains essentially incurable with a median overall survival of less than 18 months after diagnosis. A great challenge in current therapies lies in the abrogated delivery of most of the chemotherapeutic agents to the tumor location in the presence of blood-brain barrier (BBB) and blood-brain tumor barrier (BBTB). These protective barriers serve as a selectively permeable hurdle reducing the efficacy of anti-tumor drugs in GBM therapy. This work systematically gives a comprehensive review on: (i) the characteristics of the BBB and the BBTB, (ii) the influence of BBB/BBTB on drug delivery and the screening strategy of small-molecule chemotherapeutic agents with promising BBB/BBTB-permeable potential, (iii) the strategies to overcome the BBB/BBTB as well as the techniques which can lead to transient BBB/BBTB opening or disruption allowing for improving BBB/BBTB-penetration of drugs. It is hoped that this review provide practical guidance for the future development of small BBB/BBTB-permeable agents against GBM as well as approaches enhancing drug delivery across the BBB/BBTB to GBM.

Over the past several decades, nanocarriers have demonstrated diagnostic and therapeutic (i.e., theranostic) potencies in translational oncology, and some agents have been further translated into clinical trials. However, the practical application of nanoparticle-based medicine in living organisms is limited by physiological barriers (blood–tissue barriers), which significantly hampers the transport of nanoparticles from the blood into the tumor tissue. This review focuses on several approaches that facilitate the translocation of nanoparticles across blood–tissue barriers (BTBs) to efficiently accumulate in the tumor. To overcome the challenge of BTBs, several methods have been proposed, including the functionalization of particle surfaces with cell-penetrating peptides (e.g., TAT, SynB1, penetratin, R8, RGD, angiopep-2), which increases the passing of particles across tissue barriers. Another promising strategy could be based either on the application of various chemical agents (e.g., efflux pump inhibitors, disruptors of tight junctions, etc.) or physical methods (e.g., magnetic field, electroporation, photoacoustic cavitation, etc.), which have been shown to further increase the permeability of barriers.

BACKGROUND This review elucidates ongoing research, which show improved delivery of anticancer drugs alone and/ or enclosed in carriers collectively called nanomedicines to cross the BBB/ BTB to kill tumor cells and impact patient survival. We highlighted various advances in understanding the mechanism of BTB function that has an impact on anticancer therapeutics delivery. We discussed latest breakthroughs in developing pharmaceutical strategies, including nanomedicines and delivering them across BTB for brain tumor management and treatment. METHODS We performed an extensive literature search and highlighted important studies on the regulation of BTB permeability with respect to nanotech-based nanomedicines for targeted treatment of brain tumors. We have reviewed research articles that describe the development of specialized molecules and nanospheres, which carry payload of anticancer agents to brain tumor cells across the BBB/ BTB and avoid drug efflux systems. We highlighted research on the identification and development of targeted anti-cancer drug delivery to brain tumors. In addition, we discussed multimeric molecular therapeutics and nanomedicines that were encapsulated in nanospheres for treatment and monitoring of brain tumors. RESULTS In this context, we quoted our research on large conductance calcium-activated potassium channels (BKCa) and ATP-dependent potassium channels (KATP) as portals of enhanced antineoplastic drugs delivery. We showed that several innovative drug delivery agents such as liposomes, polymeric nanoparticles, dendrimers and many such tools can be utilized to improve anticancer drugs and nanomedicines across the BTB to reach brain tumor cells. CONCLUSION This review might interest both academic and drug company scientists involved in drug delivery to brain tumors. We further seek to present evidence that BTB modulators can be clinically developed as combination drug or/ and as stand-alone anticancer drugs. Eventually, it is expected that unrelenting effort from the scientific community in developing novel drug delivery methods should increase the survival rate of brain tumor patients, which is dismally low presently.

Glioblastoma (GB) is one of the most aggressive brain tumours, with a high mortality rate. Tumour heterogeneity, GB’s invasive nature, the blood–brain barrier (BBB) and resistance development offer significant challenges in devising an effective strategy to manage GB. Clinicians rely on tumour resection, radiotherapy and temozolomide (TMZ) chemotherapy, but their efficacy is hindered due to poor BBB penetration. EGFR (epidermal growth factor receptor), NF-κB, angiogenic pathways, RAS/RAF/MAPK, PI3K/Akt/mTOR, etc., play an important role in GB progression. Development in nanotechnology, pharmaceutical science and genetic engineering enables the design of drug candidates with superior efficacy and safety profiles. This review delves into recent advancements in nanoparticles, hydrogels, extracellular vesicles, microneedles and other drug delivery platforms used in GB treatment. These novel drug delivery systems achieved superior BBB penetration, tumour targeting, and controlled release and better survival outcomes in preclinical setups. This review also discusses the major translational challenges, including those of large-scale production, tumour heterogeneity, off-target effects and M2 macrophage induction. Innovative strategies focusing on drug delivery as a biological decision-making process, integrating tumour stress responses into drug carrier and system-level design principles, are discussed, outlining future prospects.

The blood–brain barrier (BBB) is a highly selective interface between the bloodstream and the brain that prevents systemically administered therapeutics from effectively reaching tumor cells. As tumors progress, this barrier undergoes structural and functional alterations, giving rise to the blood–tumor barrier (BTB)—a pathologically modified structure that, despite increased permeability, often exhibits heterogeneous and clinically insufficient drug transport. Although a new generation of therapies is promising, their therapeutic potential cannot be realized unless the challenges posed by these barriers are effectively addressed. Various pharmacological strategies were explored to enhance brain tumor drug delivery. These include receptor-mediated disruption, inhibition of efflux transporters, and the engineering of delivery platforms that leverage endogenous transport pathways—such as carrier-mediated, adsorptive-mediated, and receptor-mediated mechanisms—as well as cell-mediated drug delivery. This review synthesizes (1) the BBB and BTB’s structural characteristics; (2) the influence of the tumor microenvironment (TME) on drug delivery; (3) pharmacological strategies to enhance drug accumulation within brain tumors; (4) the integration of pharmacological methods with neurosurgical techniques to enhance drug delivery. As efforts to improve drug delivery across the BBB and BTB accelerate, this review aims to map the current landscape of pharmacological approaches for enhancing drug penetration into brain tumors.

Brain tumors are nothing but a collection of neoplasms originated either from areas within the brain or from systemic metastasized tumors of other organs that have spread to the brain. It is a leading cause of death worldwide. The presence of the blood-brain barrier (BBB), blood-brain tumor barrier (BBTB), and some other factors may limit the entry of many potential therapeutics into the brain tissues in tumor area at the therapeutic concentration required for satisfying effectiveness. Liposomes are taking an active role in delivering many drugs through the BBB into the tumor due to their nanosize and their physiological compatibility. Further, this colloidal carrier can encapsulate both lipophilic and hydrophilic drugs due to its unique structure. The surface of the liposomes can be modified with various ligands that are very specific to the numerous receptors overexpressed onto the BBB as well as onto the diseased tumor surface site (i.e., BBTB) to deliver selective drugs into the tumor site. Moreover, the enhanced permeability and retention (EPR) effect can be an added advantage for nanosize liposomes to concentrate into the tumor microenvironment through relatively leaky vasculature of solid tumor in the brain where no restriction of penetration applies compared to normal BBB. Here in this review, we have tried to compilethe recent advancement along with the associated challenges of liposomes containing different anticancer chemotherapeutics across the BBB/BBTB for the treatment of gliomas that will be very helpful for the readers for better understanding of different trends of brain tumor targeted liposomes-based drug delivery and for pursuing fruitful research on the similar research domain.

Glioblastoma multiforme (also known as glioblastoma; GBM) is one of the most malignant types of brain tumors that occurs in the CNS. Treatment strategies for glioblastoma are majorly comprised of surgical resection, radiotherapy, and chemotherapy along with combination therapy. Treatment of GBM is itself a tedious task but the involved barriers in GBM are one of the main impediments to move one step closer to the treatment of GBM. Basically, two of the barriers are of utmost importance in this regard, namely blood brain barrier (BBB) and blood brain tumor barrier (BBTB). This review will address different challenges and barriers in the treatment of GBM along with their etiology. The role and recent progress of lipid-based nanocarriers like liposomes, solid lipid nanocarriers (SLNs), nanostructured lipid carriers (NLCs), lipoplexes, and lipid hybrid carriers in the effective management of GBM will be discussed in detail. Graphical Abstract

Glioblastoma (GBM) is the most common primary brain tumor and carries a grave prognosis. Despite years of research investigating potentially new therapies for GBM, the median survival rate of individuals with this disease has remained fairly stagnant. Delivery of drugs to the tumor site is hampered by various barriers posed by the GBM pathological process and by the complex physiology of the blood-brain and blood–cerebrospinal fluid barriers. These anatomical and physiological barriers serve as a natural protection for the brain and preserve brain homeostasis, but they also have significantly limited the reach of intraparenchymal treatments in patients with GBM. In this article, the authors review the functional capabilities of the physical and physiological barriers that impede chemotherapy for GBM, with a specific focus on the pathological alterations of the blood-brain barrier (BBB) in this disease. They also provide an overview of current and future methods for circumventing these barriers in therapeutic interventions. Although ongoing research has yielded some potential options for future GBM therapies, delivery of chemotherapy medications across the BBB remains elusive and has limited the efficacy of these medications.

Glioblastoma remains resistant to most conventional treatments. Despite scientific advances in the past three decades, there has been a dearth of effective new treatments. New approaches to drug delivery and clinical trial design are needed. We discuss how the blood–brain barrier and tumor microenvironment pose challenges for development of effective therapies for glioblastoma. Next, we discuss treatments in development that aim to overcome these barriers, including novel drug designs such as nanoparticles and antibody–drug conjugates, novel methods of drug delivery, including convection-enhanced and intra-arterial delivery, and novel methods to enhance drug penetration, such as blood–brain barrier disruption by focused ultrasound and laser interstitial thermal therapy. Lastly, we address future opportunities, positing combination therapy as the best strategy for effective treatment, neoadjuvant and window-of-opportunity approaches to simultaneously enhance therapeutic effectiveness with interrogation of on-treatment biologic endpoints, and adaptive platform and basket trials as imperative for future trial design. New approaches to GBM treatment should account for the blood-brain barrier and immunosuppression by improving drug delivery, combining treatments, and integrating novel clinical trial designs.

Glioblastoma is known as the most aggressive primary brain tumor in adults and it is still largely not curable, with a median survival of approximately 15 months when standard multimodal therapy is applied. The standard treatment nowadays is maximal safe surgical resection, associated with radiotherapy and temozolomide. Treatment effectiveness is limited not only by an impassable blood–brain barrier (BBB) to drug delivery to the brain, but also by the heterogeneity of the tumors and by intrinsic or gained drug resistance – resulting in a certain and inescapable tumor relapse. Therefore, novel drug delivery systems are being designed to overcome the BBB and improve therapeutic efficacy. These approaches include nanoparticle-mediated delivery systems, convection-enhanced intratumoral infusion, implantable drug-releasing devices, and noninvasive focused ultrasound technology induced transient disruption of the BBB. These approaches are designed to enhance local drug exposure and to reduce systemic toxicity with promising preclinical and early clinical results. However, many clinical and technical challenges remain, especially the need for safety, homogeneous drug delivery, and translation of these advances into effective clinical therapies. Current glioblastoma treatment landscape and opportunities include maturing delivery systems, novel therapeutic approaches including targeted molecular therapies and immunotherapy, as well as personalized regimens. This multidisciplinary modality may have the capacity to help not only GBM patients but others as well through a multimodal approach of targeted drug delivery and innovative therapy in the long run in order to improve clinical outcomes of GBM in patients.

The blood-brain barrier (BBB) is a highly selective network of various cell types that acts as a filter between the blood and the brain parenchyma. Because of this, the BBB remains a major obstacle for drug delivery to the central nervous system (CNS). In recent years, there has been a focus on developing various modifiable platforms, such as monoclonal antibodies (mAbs), nanobodies (Nbs), peptides, and nanoparticles, as both therapeutic agents and carriers for targeted drug delivery to treat brain cancers and diseases. Methods for bypassing the BBB can be invasive or noninvasive. Invasive techniques, such as transient disruption of the BBB using low pulse electrical fields and intracerebroventricular infusion, lack specificity and have numerous safety concerns. In this review, we will focus on noninvasive transport mechanisms that offer high levels of biocompatibility, personalization, specificity and are regarded as generally safer than their invasive counterparts. Modifiable platforms can be designed to noninvasively traverse the BBB through one or more of the following pathways: passive diffusion through a physio-pathologically disrupted BBB, adsorptive-mediated transcytosis, receptor-mediated transcytosis, shuttle-mediated transcytosis, and somatic gene transfer. Through understanding the noninvasive pathways, new applications, including Chimeric Antigen Receptors T-cell (CAR-T) therapy, and approaches for drug delivery across the BBB are emerging.

Glioma is a fatal disease with limited treatment options and very short survival. Although chemotherapy is one of the most important strategies in glioma treatment, it remains extremely clinically challenging largely due to the blood-brain barrier (BBB) and the blood-brain tumor barrier (BBTB). Thus, the development of nanoparticles with both BBB and BBTB penetrability, as well as glioma-targeting feature, is extremely important for the therapy of glioma. New findings in nanomedicine are promoting the development of novel biomaterials. Herein, we designed a red blood cell membrane-coated solid lipid nanoparticle (RBCSLN)-based nanocarrier dual-modified with T7 and NGR peptide (T7/NGR-RBCSLNs) to accomplish these objectives. As a new kind of biomimetic nanovessels, RBCSLNs preserve the complex biological functions of natural cell membranes while possessing physicochemical properties that are needed for efficient drug delivery. T7 is a ligand of transferrin receptors with seven peptides that is able to circumvent the BBB and target to glioma. NGR is a peptide ligand of CD13 that is overexpressed during angiogenesis, representing an excellent glioma-homing property. After encapsulating vinca alkaloid vincristine as the model drug, T7/NGR-RBCSLNs exhibited the most favorable antiglioma effects in vitro and in vivo by combining the dual-targeting delivery effect. The results demonstrate that dual-modified biomimetic nanoparticles provide a potential method to improve drug delivery to the brain, hence increasing glioma therapy efficacy.

Glioblastoma multiforme (GBM) is an aggressive brain cancer with a poor prognosis and few treatment options. Here, building on the observation of elevated lactate (LA) in resected GBM, we develop biomimetic therapeutic nanoparticles (NPs) that deliver agents for LA metabolism-based synergistic therapy. Because our self-assembling NPs are encapsulated in membranes derived from glioma cells, they readily penetrate the blood-brain barrier and target GBM through homotypic recognition. After reaching the tumors, lactate oxidase in the NPs converts LA into pyruvic acid (PA) and hydrogen peroxide (H2O2). The PA inhibits cancer cell growth by blocking histones expression and inducing cell-cycle arrest. In parallel, the H2O2 reacts with the delivered bis[2,4,5-trichloro-6-(pentyloxycarbonyl)phenyl] oxalate to release energy, which is used by the co-delivered photosensitizer chlorin e6 for the generation of cytotoxic singlet oxygen to kill glioma cells. Such a synergism ensures strong therapeutic effects against both glioma cell-line derived and patient-derived xenograft models. Targeting cancer-associated metabolism is evolving as a promising approach for cancer therapy. Here, the authors generate cancer cell-membrane encapsulated nanoparticles to induce cell cycle arrest and cytotoxicity in lactate-high cancer cells, reducing tumourigensis in glioblastoma cell-line and patient-derived models.

Nanosuspensions, as a new drug delivery system for insoluble drugs, are only composed of a drug and a small amount of stabilizer, which is dispersed in an aqueous solution with high drug-loading, small particle size, high dispersion, and large specific surface area. It can significantly improve the dissolution, bioavailability, and efficacy of insoluble drugs. In this study, paclitaxel nanosuspensions ((PTX)NS) were prepared by an ultrasonic precipitation method, with the characteristics of simple preparation and easy repetition. With the help of a homologous targeting mechanism, a kind of glioma C6 cancer cell membrane (CCM)-coated (PTX)NS was developed and modified with DWSW peptide to obtain DWSW-CCM-(PTX)NS with the functions of BBB penetration and tumor targeting. The results showed that the cancer cell membrane could effectively camouflage the nanosuspensions so that it was not cleared by the immune system and could cross the blood-brain-barrier (BBB) and selectively target tumor tissues. Cell uptake experiments and in vivo imaging confirmed that the uptake of DWSW-CCM-(PTX)NS by tumor cells and the distribution in intracranial gliomas increased. Cytotoxicity test and in vivo anti-glioma studies showed that DWSW-CCM-(PTX)NS could significantly inhibit the growth of glioma cells and significantly prolong the survival time of glioma-bearing mice. Finally, the cancer cell membrane coating endowed the nanosuspensions with the biological properties of homologous adhesion and immune escape. This study provides an integrated solution for improving the targeting of nanosuspensions and demonstrates the encouraging potential of biomimetic nanosuspensions applicable to tumor therapy.

Glioblastoma multiforme (GBM) is one of the most fatal malignancies due to the existence of blood-brain barrier (BBB) and the difficulty to maintain an effective drug accumulation in deep GBM lesions. Here we present a biomimetic nanogel system that can be precisely activated by near infrared (NIR) irradiation to achieve BBB crossing and deep tumor penetration of drugs. Synthesized by crosslinking pullulan and poly(deca-4,6-diynedioic acid) (PDDA) and loaded with temozolomide and indocyanine green (ICG), the nanogels are inert to endogenous oxidative conditions but can be selectively disintegrated by ICG-generated reactive oxygen species upon NIR irradiation. Camouflaging the nanogels with apolipoprotein E peptide-decorated erythrocyte membrane further allows prolonged blood circulation and active tumor targeting. The precisely controlled NIR irradiation on tumor lesions excites ICG and deforms the cumulated nanogels to trigger burst drug release for facilitated BBB permeation and infiltration into distal tumor cells. These NIR-activatable biomimetic nanogels suppress the tumor growth in orthotopic GBM and GBM stem cells-bearing mouse models with significantly extended survival. Effective drug accumulation in deep glioblastoma multiforme (GBM) lesions remains challenging due to the blood brain barrier. Here, the authors develop a biomimetic nanogel system activated by near infrared irradiation and show high efficacy in orthotopic GBM and GBM stem cells-bearing mouse models.

Abstract Glioblastoma multiforme (GBM) is an aggressive brain tumor with poor prognosis and high mortality, with no curative treatment to date as limited trafficking across the blood–brain barrier (BBB) combined with tumor heterogeneity often leads to therapeutic failure. Although modern medicine poses a wide range of drugs that are otherwise efficacious in treating other tumors, they often do not achieve therapeutic concentrations in the brain, hence driving the need for more effective drug delivery strategies. Nanotechnology, an interdisciplinary field, has been gaining immense popularity in recent years for remarkable advancements such as nanoparticle (NP) drug carriers, which possess extraordinary versatility in modifying surface coatings to home in on target cells, including those beyond the BBB. In this review, we will be highlighting recent developments in biomimetic NPs in GBM therapy and how these allowed us to overcome the physiological and anatomical challenges that have long plagued GBM treatment.

… inflammatory homing pathways and adhesion molecules to … In summary, Biom-NCs for glioblastoma have evolved toward … Biomimetic nanocarriers mimic natural cell membranes to …

Glioma is one of the most common malignant tumors with characteristics of strong invasion and high postoperative recurrence rate, which seriously threatens human health. Nanoparticles as an emerging drug delivery system have promoted the development of glioma therapy. However, blocking of nanoparticles by the blood-brain barrier is still serious problem for the use of nanoparticles in glioma therapy. In this context, traditional nanoparticles are dressed with natural cell membranes to prepare biomimetic nanoparticles. Biomimetic nanoparticles show longer blood circulation time, excellent homologous targeting and outstanding immune escape capacity, which significantly improve the accumulation of nanoparticles at the tumor site. The therapeutic effect for glioma has been raised to an advanced level. This review focuses on the preparations and applications of cell membrane-functionalized biomimetic nanoparticles, as while as the advantages and problems of biomimetic nanoparticles in the treatment of glioma. In particular, the approach of using biomimetic nanoparticles to cross the blood-brain barrier is analyzed, in the hope of providing new ideas for further developments in crossing the blood-brain barrier and in glioma therapy.

Glioma-associated macrophages (GAMs) are central mediators of immune evasion and therapeutic resistance in glioblastoma multiforme (GBM) due to their tumor-promoting M2 phenotype and loss of phagocytic activity toward tumor cells. Activating GAMs represent an attractive therapeutic strategy against GBM, but it is hindered by the lack of effective therapies and insufficient drug exposure. Herein, an engineered biomimetic delivery system (SIRPα@BSA/PTX) is developed by enveloping albumin-bound paclitaxel (BSA/PTX) with a genetically engineered melanoma cell membrane expressing SIRPα variants to activate GAMs for improved GBM therapy. SIRPα@BSA/PTX efficiently penetrates the blood-brain barrier (BBB) to accumulate in GBM by leveraging the brain tropism of the melanoma cell membrane. Subsequently, SIRPα variants on the cell membrane, along with PTX in the inner core, synergistically enhance the repolarization and phagocytic abilities of GAMs. In vivo studies show that SIRPα@BSA/PTX significantly suppresses tumor growth and recurrence in orthotopic and postoperative murine GBM models and achieves 100% mouse survival when combined with immune checkpoint inhibitors. Transcriptome analysis of clinical GBM patient samples treated with SIRPα@BSA/PTX also reveals remarkable immune activation signatures, suggesting the great potential of nanoenabled macrophage-based immunotherapy for brain tumors.

Glioblastoma (GBM), the most prevalent primary brain tumor in adults, remains highly challenging due to its invasive nature, limited treatment effectiveness, and short median survival durations. Standard of care includes surgery, radiation, chemotherapy, and tumor treating fields; however, there has been little improvement in survival rates. Biomimetic nanoparticles (NPs), coated with cell membranes and endogenous components, have immense potential for improving chemotherapy in GBM, by imitating cellular architecture and eluding immune clearance. With more individualized and efficient drug delivery, immunotherapeutic approaches and biomimetic NPs may increase patient survival rates. This article summarizes the main research on biomimetic NPs for GBM therapy, focusing on the classification, mechanisms, advantages, and challenges, along with the advancements in the development of GBM vaccines.

… major obstacles in the clinical treatment of glioblastoma (GBM). To … The BMN is engineered with biomimetic cell membranes that … for deep-seated gliomas under external light irradiation. …

Introduction Glioblastoma multiforme (GBM), a highly invasive and prognostically challenging brain cancer, poses a significant hurdle for current treatments due to the existence of the blood-brain barrier (BBB) and the difficulty to maintain an effective drug accumulation in deep GBM lesions. Methods We present a biomimetic nanoplatform with angiopep-2-modified macrophage membrane, loaded with indocyanine green (ICG) templated self-assembly of SN38 (AM-NP), facilitating active tumor targeting and effective blood-brain barrier penetration through specific ligand-receptor interaction. Results Upon accumulation at tumor sites, these nanoparticles achieved high drug concentrations. Subsequent combination of laser irradiation and release of chemotherapy agent SN38 induced a synergistic chemo-photothermal therapy. Compared to bare nanoparticles (NPs) lacking cell membrane encapsulation, AM-NPs significantly suppressed tumor growth, markedly enhanced survival rates, and exhibited excellent biocompatibility with minimal side effects. Conclusion This NIR-activatable biomimetic camouflaging macrophage membrane-based nanoparticles enhanced drug delivery targeting ability through modifications of macrophage membranes and specific ligands. It simultaneously achieved synergistic chemo-photothermal therapy, enhancing treatment effectiveness. Compared to traditional treatment modalities, it provided a precise, efficient, and synergistic method that might have contributed to advancements in glioblastoma therapy.

Abstract Active components of natural products, which include paclitaxel, curcumin, gambogic acid, resveratrol, triptolide and celastrol, have promising anti-inflammatory, antitumor, anti-oxidant, and other pharmacological activities. However, their clinical application is limited due to low solubility, instability, low bioavailability, rapid metabolism, short half-life, and strong off-target toxicity. To overcome these drawbacks, cell membrane-based biomimetic nanosystems have emerged that avoid clearance by the immune system, enhance targeting, and prolong drug circulation, while also improving drug solubility and bioavailability, enhancing drug efficacy, and reducing side effects. This review summarizes recent advances in the preparation and coating of cell membrane-coated biomimetic nanosystems and in their applications to disease for targeted natural products delivery. Current challenges, limitations, and prospects in this field are also discussed, providing a research basis for the development of multifunctional biomimetic nanosystems for natural products.

Biomimetic nanosystems and vesicles have arisen as a novel approach to design vesicular transport systems with diverse therapeutic potential. The ‘biomimetic’ strategy involves the integration of cell membrane components into lipid bilayers, conferring them with biological properties originating from the cell of origin. Until now, most studies have primarily focused on the evaluation of the biological activity and function of different biomimetic nanosystems with limited exploration of the engineering parameters selected and little characterization of their features at the molecular level. This study aimed to address this knowledge gap by describing a preparation method for biomimetic lipid vesicles using traditional liposome fabrication principles and cellular components exclusively derived from glioblastoma (GL261) cell membrane proteins. Critical engineering parameters were studied, such as bilayer lipid and cholesterol content, the degree of surface PEGylation and some processing aspects like purification and quantification. Following fabrication, the GL261‐derived vesicles underwent purification using size exclusion chromatography to separate unbound proteins from the vesicles. Subsequently, the GL261‐derived vesicles were characterized by cryo‐EM and differential scanning calorimetry (DSC) to assess their morphological and thermal properties, respectively. Both cholesterol and PEGylated lipid content played an important role on the structural and colloidal features of the biomimetic vesicles (BV). Mass spectroscopy (LC‐MS/MS) revealed the proteomic signature of the fabricated vesicles at the molecular level. Collectively, these findings advance the rational engineering of BV and offer an in‐depth proteomic framework that reveals their molecular identity and functional potential. By connecting the design principles of fabrication with the molecular features of the vesicles, this study paves the way for next‐generation biomimetic platforms for cancer chemotherapy, immunomodulation and cancer vaccination.

Glioblastoma (GBM) is the most aggressive intracranial tumor that occurs in the central nervous system (CNS) and has no effective treatment due to the fact of drug resistance. To combat drug resistance, TMZ is generally administrated in combination with other chemotherapeutic drugs. Unfortunately, drug combinations used to date only show modest improvements in anti‐tumor effects and have increased toxicity. Herein, an ApoE peptide decorated GBM cancer cell membrane camouflaged nanomedicine (AMNPs@TMZ+LM) to specifically co‐deliver TMZ and the MGMT inhibitor lomeguatrib (LM) for combinatorial GBM treatment is developed. Incorporation of LM not only effectively suppresses the repair of damaged DNA, but also inhibits tumor cell proliferation by inducing cell cycle arrest. Importantly, this biomimetic nanomedicine achieves high BBB penetration and enhances sensitivity to both TMZ‐resistant (U251‐TR) and GBM stem cells (GSCs). Notably, AMNPs@TMZ+LM results in significant inhibition of the growth of orthotopically implanted U251‐TR tumor in mice. In comparison, treatment with single drug loaded nanomedicines results in compromised anti‐GBM effects. Histological analyses and blood parameter studies show good biocompatibility of the nanomedicine. Hence, this biomimetic nanomedicine provides a potential new approach to overcome the limitations of current GBM chemotherapy regimens by co‐delivery of TMZ and the MGMT inhibitor LM.

Glioma, the most common primary brain tumor, is highly invasive and grows rapidly. As such, the survival of glioma patients is relatively short, highlighting the vital importance of timely diagnosis and treatment of glioma. However, the blood brain barrier (BBB) and the non-targeting delivery systems of contrast agents and drugs greatly hinder the effective glioma imaging and therapy. Fortunately, in recent years, investigators have constructed various biomimetic delivery platforms utilizing the exceptional advantages of biomimetic nanocomposites, such as immune evasion, homologous targeting ability, and BBB penetrating ability, to achieve efficient and precise delivery of substances to glioma sites for improved diagnosis and treatment. In this concept, we present the application of these biomimetic nanocomposites in fluorescence imaging (FI), magnetic resonance imaging (MRI), and multi-modal imaging, as well as in chemotherapy, phototherapy, and combined therapy for glioma. Lastly, we provide our perspective on this research field.

Advances in phototheranostics revolutionized glioma intraoperative fluorescence imaging and phototherapy. However, the lack of desired active targeting agents for crossing the blood-brain barrier (BBB) significantly compromises the theranostic efficacy. In this study, biomimetic proteolipid nanoparticles (NPs) with U.S. Food and Drug Administration (FDA)-approved indocyanine green (ICG) were constructed to allow fluorescence imaging, tumor margin detection, and phototherapy of orthotopic glioma in mice. By embedding glioma cell membrane proteins into NPs, the obtained biomimetic ICG-loaded liposome (BLIPO-ICG) NPs could cross BBB and actively reach glioma at the early stage thanks to their specific binding to glioma cells due to their excellent homotypic targeting and immune escaping characteristics. High accumulation in the brain tumor with a signal to background ratio of 8.4 was obtained at 12 h post-injection. At this time point, the glioma and its margin were clearly visualized by near-infrared fluorescence imaging. Under the imaging guidance, the glioma tissue could be completely removed as a proof of concept. In addition, after NIR laser irradiation (1 W/cm2, 5 min), the photothermal effect exerted by BLIPO-ICG NPs efficiently suppressed glioma cell proliferation with a 94.2% tumor growth inhibition. No photothermal damages of normal brain tissue and treatment-induced side effects were observed. These results suggest that the biomimetic proteolipid NP is a promising phototheranostic nanoplatform for brain-tumor-specific imaging and therapy.

Abstract The main treatment measure currently used for glioma treatment is chemotherapy; the biological barrier of solid tumors hinders the deep penetration of nanomedicines and limits anticancer therapy. Furthermore, the poor solubility of many chemotherapeutic drugs limits the efficacy of antitumor drugs. Therefore, improving the solubility of chemotherapeutic agents and drug delivery to tumor tissues through the blood–brain barrier (BBB) and blood–brain tumor barrier (BBTB) are major challenges in glioma treatment. Nanostructured lipid carriers (NLCs) have high drug loading capacity, high stability, and high in vivo safety; moreover, they can effectively improve the solubility of insoluble drugs. Therefore, in this study, we used solvent volatilization and ultrasonic melting methods to prepare dihydroartemisinin nanostructured lipid carrier (DHA-NLC). We further used the glioma C6 cancer cell (CC) membrane to encapsulate DHA-NLC owing to the homologous targeting mechanism of the CC membrane; however, the targeting ability of the CC membrane was weak. We accordingly used targeting ligands for modification, and developed a bionanostructured lipid carrier with BBB and BBTB penetration and tumor targeting abilities. The results showed that DHA-loaded NGR/CCNLC (asparagine–glycine–arginine, NGR) was highly targeted, could penetrate the BBB and BBTB, and showed good anti-tumor effects both in vitro and in vivo, which could effectively prolong the survival time of tumor-bearing mice. Thus, the use of DHA-loaded NGR/CCNLC is an effective strategy for glioma treatment and has the potential to treat glioma.

… to tumor sites by a tumor-targeting carrier. To explore Dac for glioblastoma (GBM) therapy while avoiding its toxicity, we developed a new brain tumor-targeting drug delivery system self-…

Glioblastoma (GBM) is a highly aggressive and lethal form of primary brain cancer. Numerous barriers exist to the effective treatment of GBM including the tightly controlled interface between the blood stream and central nervous system termed the ‘neurovascular unit’, a narrow and tortuous tumor extracellular space containing a dense meshwork of proteins and glycosaminoglycans, and genomic heterogeneity and instability. A major goal of GBM therapy is achieving sustained drug delivery to glioma cells while minimizing toxicity to adjacent neurons and glia. Targeted nanotherapeutics have emerged as promising drug delivery systems with the potential to improve pharmacokinetic profiles and therapeutic efficacy. Some of the key cell surface molecules that have been identified as GBM targets include the transferrin receptor, low-density lipoprotein receptor-related protein, αvβ3 integrin, glucose transporter(s), glial fibrillary acidic protein, connexin 43, epidermal growth factor receptor (EGFR), EGFR variant III, interleukin-13 receptor α chain variant 2, and fibroblast growth factor-inducible factor 14. However, most targeted therapeutic formulations have yet to demonstrate improved efficacy related to disease progression or survival. Potential limitations to current targeted nanotherapeutics include: (i) adhesive interactions with non-target structures, (ii) low density or prevalence of the target, (iii) lack of target specificity, and (iv) genetic instability resulting in alterations of either the target itself or its expression level in response to treatment. In this review, we address these potential limitations in the context of the key GBM targets with the goal of advancing the understanding and development of targeted nanotherapeutics for GBM.

… nanoparticles (UCNPs), herein, we have developed a dual-targeting nanoprobe (ANG/PEG-UCNPs) to cross … In summary, a novel BBB and glioblastoma dual-targeted brain nanoprobe …

… nanoparticles (TLN) for treating glioblastoma, the most aggressive brain tumor whose treatment is limited by a low blood brain barrier (… from liquid state nanoparticles. During cytotoxicity …

… nanoparticles combined with drugs and CAR T cell therapy as a novel therapeutic strategy for glioma… nanoparticles cross the BBB, target glioma, and deliver drugs is illustrated in Fig. 3. …

The blood-brain barrier (BBB) poses a formidable challenge to efficient drug delivery into the brain. One promising approach involves leveraging receptor-mediated transcytosis facilitated by Angiopep-2 peptide (Ang-2)-conjugated nanoparticles. However, the precise impact of Ang-2 density on BBB penetration remains poorly understood. In this study, we developed a versatile polymeric nanoparticle system with tuneable Ang-2 surface density and systemically examined its influence on BBB penetration through various in vitro assays and an in vivo study. Our findings revealed a nuanced relationship between Ang-2 surface density and BBB penetration across the different experimental setups. In 2D cell culture, we observed a positive correlation between Ang-2 surface density and cellular association in hCMEC/D3 cells, characterized by a distinctive inflection point. Conversely, in the Transwell model, higher Ang-2 density correlated negatively with BBB penetration, whereas the BBB-GBM-on-a-chip showed the opposite trend. These disparities may arise from differences in avidity under static versus dynamic conditions, potentially modulating nanoparticle interactions due to fluidic forces. In vivo studies revealed that higher Ang-2 densities facilitated nanoparticle transport across the BBB, consistent with the findings of the BBB-GBM-on-a-chip model. Furthermore, loading doxorubicin into nanoparticles with optimal Ang-2 density resulted in controlled pH-responsive release and enhanced anticancer effect against U87 GBM cells in both 2D cell cultures and a 3D BBB-GBM-on-a-chip model. These results underscore the critical importance of optimizing Ang-2 surface density for efficient BBB penetration and emphasize the utility of dynamic models in preclinical in vitro assessment of novel nanoparticle formulations for targeted delivery to the brain.

Glioblastoma is the most destructive type of brain cancer. The blood-brain barrier (BBB) is a tremendous obstacle that hinders therapeutic agents, such as chemical drugs and antibodies, from reaching glioblastoma tissues. Meanwhile, the abnormal microenvironment of glioblastoma extremely restricts the expected therapeutic effects of accumulated drugs. Therefore, in the present study, BBB-regulating nanovesicles (BRN) are developed to achieve targeted and controlled BBB regulation, carrying adenosine 2A receptor (A2AR) agonists and perfluorocarbon (PF). The red-blood-cell membrane (RBCM) is included on the outside to avoid the premature release of therapeutic agents. In the presence of ultrasonication (US), A2AR agonists are released and induce effects on both F-actin and tight junctions of endothelial cells. Subsequently, BBB permeability is temporarily increased and enables small molecules and nanoparticles to enter brain parenchymal tissues. The high affinity between manganese dioxide and temozolomide (TMZ) is utilized to form multifunctional nanoparticles to ameliorate the hypoxic microenvironment, which yields improved glioblastoma inhibition combined with radiotherapy. Moreover, with the aid of targeted BBB regulation, programmed death ligand-1 (PD-L1) antibody induces a tumor-specific immune response. Taken together, the findings suggest that synergistic combination may have the potential in amplifying the therapeutic efficacies of clinical drugs and immune checkpoint blockade antibodies to overcome the therapeutic resistance of glioblastoma.

Glioblastoma (GBM) is one of the deadliest and most invasive brain cancers/gliomas, and there is currently no established way to treat this disease. The treatment of GBM typically involves intracranial surgery followed by chemotherapy. However, the blood-brain barrier (BBB) impedes the delivery of the chemotherapeutic drug, making the treatment challenging. In this study, we embedded a chemotherapeutic drug and other nanomaterials into a nanobubble (NB), utilized active tracking and other guidance mechanisms to guide the nanocomposite to the tumor site, and then used high-intensity focused ultrasound oscillation to burst the nanobubbles, generating a transient cavitation impact on the BBB and allowing the drug to bypass it and reach the brain. FePt enhances the resolution of T2-weighted magnetic resonance imaging images and has magnetic properties that help guide the nanocomposite to the tumor location. FePt nanoparticles were loaded into the hydrophobic core of the NBs along with doxorubicin to form a bubble-based drug delivery system (Dox-FePt@NB). The surface of the NBs is modified with a targeting ligand, transferrin (Dox-FePt@NB-Tf), giving the nanocomposite active tracking abilities. The Dox-FePt@NB-Tf developed in the present study represents a potential breakthrough in GBM treatment through improved drug delivery and biological imaging.

Nuclear factor-κB (NF-κB) is a transcription factor that regulates various genes that mediate various cellular activities, including propagation, differentiation, motility, and survival. Abnormal activation of NF-κB is a common incidence in several cancers. Glioblastoma multiforme (GBM) is the most aggressive brain cancer described by high cellular heterogeneity and almost unavoidable relapse following surgery and resistance to traditional therapy. In GBM, NF-κB is abnormally activated by various stimuli. Its function has been associated with different processes, including regulation of cancer cells with stem-like phenotypes, invasion of cancer cells, and radiotherapy resistance identification of mesenchymal cells. Even though multimodal therapeutic approaches such as surgery, radiation therapy, and chemotherapeutic drugs are used for treating GBM, however; the estimated mortality rate for GBM patients is around 1 year. Therefore, it is necessary to find out new therapeutic approaches for treating GBM. Many studies are focusing on therapeutics having less adverse effects owing to the failure of conventional chemotherapy and targeted agents. Several studies of compounds suggested the involvement of NF-κB signaling pathways in the growth and development of a tumor and GBM cell apoptosis. In this review, we highlight the involvement of NF-κB signaling in the molecular understanding of GBM and natural compounds targeting NF-κB signaling.

Immune checkpoint blockade (ICB) therapy has shown tremendous promises in the treatment of various types of tumors. However, ICB therapy with antibodies appears to be less effective for glioma, partly owing to the existence of the blood-brain barrier (BBB) that impedes the entrance of therapeutics including most proteins to the central nervous system (CNS). Herein, considering the widely existing nicotinic acetylcholine receptors (nAChRs) and choline transporters (ChTs) on the surface of BBB, a choline analogue 2-methacryloyloxyethyl phosphorylcholine (MPC) is employed to fabricate the BBB-crossing copolymer via free-radical polymerization, followed by conjugation with antiprogrammed death-ligand 1 (anti-PD-L1) via a pH-sensitive traceless linker. The obtained nanoparticles exhibit significantly improved BBB-crossing capability owing to the receptor-mediated transportation after intravenous injection in an orthotopic glioma tumor model. Within the acidic glioma microenvironment, anti-PD-L1 would be released from such pH-responsive nanoparticles, further triggering highly effective ICB therapy of glioma to significantly prolong animal survival. This work thus realizes glioma microenvironment responsive BBB-crossing delivery of ICB antibodies, promising for the next generation immunotherapy of glioma.

In humans, glioblastoma is the most prevalent primary malignant brain tumor. Usually, glioblastoma has specific characteristics, such as aggressive cell proliferation and rapid invasion of surrounding brain tissue, leading to a poor patient prognosis. The current therapy—which provides a multidisciplinary approach with surgery followed by radiotherapy and chemotherapy with temozolomide—is not very efficient since it faces clinical challenges such as tumor heterogeneity, invasiveness, and chemoresistance. In this respect, natural substances in the diet, integral components in the lifestyle medicine approach, can be seen as potential chemotherapeutics. There are several epidemiological studies that have shown the chemopreventive role of natural dietary compounds in cancer progression and development. These heterogeneous compounds can produce anti-glioblastoma effects through upregulation of apoptosis and autophagy; allowing the promotion of cell cycle arrest; interfering with tumor metabolism; and permitting proliferation, neuroinflammation, chemoresistance, angiogenesis, and metastasis inhibition. Although these beneficial effects are promising, the efficacy of natural compounds in glioblastoma is limited due to their bioavailability and blood–brain barrier permeability. Thereby, further clinical trials are necessary to confirm the in vitro and in vivo anticancer properties of natural compounds. In this article, we overview the role of several natural substances in the treatment of glioblastoma by considering the challenges to be overcome and future prospects.

Simple Summary Glioblastoma (GBM) is a tumor of the brain or spinal cord with poor clinical prognosis. Current interventions, such as chemotherapy and surgical tumor resection, are constrained by tumor invasion and cancer drug resistance. Dietary natural substances are therefore evaluated for their potential as agents in GBM treatment. Various substances found in fruits, vegetables, and other natural products restrict tumor growth and induce GBM cell death. These preclinical effects are promising but remain constrained by natural substances’ varying pharmacological properties. While many of the reviewed substances are available as over-the-counter supplements, their anti-GBM efficacy should be corroborated by clinical trials moving forward. Abstract Glioblastoma (GBM) is an aggressive, often fatal astrocyte-derived tumor of the central nervous system. Conventional medical and surgical interventions have greatly improved survival rates; however, tumor heterogeneity, invasiveness, and chemotherapeutic resistance continue to pose clinical challenges. As such, dietary natural substances—an integral component of the lifestyle medicine approach to chronic diseases—are examined as potential chemotherapeutic agents. These heterogenous substances exert anti-GBM effects by upregulating apoptosis and autophagy, inducing cell cycle arrest, interfering with tumor metabolism, and inhibiting proliferation, neuroinflammation, chemoresistance, angiogenesis, and metastasis. Although these beneficial effects are promising, natural substances’ efficacy in GBM is constrained by their bioavailability and blood–brain barrier permeability; various chemical formulations are proposed to improve their pharmacological properties. Many of the reviewed substances are available as over-the-counter dietary supplements, underscoring their viability as lifestyle interventions. However, clinical trials remain necessary to substantiate the in vitro and in vivo properties of natural substances.

Natural Products (NPs) are increasingly utilized worldwide for their potential therapeutic benefits, including central nervous system (CNS) disorders. Studies have shown açai berries mitigating Parkinson’s disease progression through dopaminergic neuroprotection via Nrf-2 HO-1 pathways. Ashwagandha, an evergreen shrub, has shown potential as a therapeutic for neurodegenerative disorders via axonal regeneration in Aβ25-35-treated cortical neurons in vitro. In most cases, promising NPs are tested using in vitro assays or simpler systems during the early stages of drug discovery. However, a critical challenge lies in the lack of data on blood-brain barrier (BBB) penetration, which is a significant determinant for the successful development of CNS drugs. Our first goal was to test our in-house NP constituent library via the Parallel Artificial Membrane Permeability Assay (PAMPA-BBB), with the aim of understanding their BBB-penetration potential. Of the constituents tested, 255 were found to have moderate to high BBB permeability. Our next goal was to understand if these compounds could exhibit CNS toxicity. Neuronal viability and neurite outgrowth assays were performed with this subset to identify compounds with neurotoxicity potential. Around 35% of compounds tested showed neurite outgrowth inhibition. The habitual and widespread consumption of NPs underscores the importance of subjecting this subset of compounds to additional testing and validation in vivo to ascertain their potential detrimental effects. Understanding BBB permeability and assessing neurotoxicity mechanisms of NPs will significantly benefit the CNS drug discovery community.

Alzheimer’s disease (AD) is a progressive neurodegenerative disease that disrupts cognitive function and severely affects the quality of life. Existing drugs only improve cognitive function and provide temporary relief of symptoms but do not stop or delay disease progression. Recently, natural medicines, especially Chinese herbal medicines, have gained attention in the treatment of AD due to their antioxidant, anti-inflammatory, and neuroprotective effects. However, conventional oral dosage forms lack brain specificity and have side effects that lead to poor patient compliance. Utilizing nanomedicine is a promising approach to improve brain specificity, bioavailability, and patient compliance. This review evaluates recent advances in the treatment of AD with nanoparticles containing various natural medicines. This review highlights that nanoparticles containing natural medicines are a promising strategy for the treatment of AD. It is believed that this technology can be translated into the clinic, thereby providing opportunities for AD patients to participate in social activities.

OBJECTIVEMany pharmaceutical agents are highly potent but are unable to exert therapeutic activity against disorders of the central nervous system (CNS), because the blood-brain barrier (BBB) impedes their brain entry. One such agent is bortezomib (BZM), a proteasome inhibitor that is approved for the treatment of multiple myeloma. Preclinical studies established that BZM can be effective against glioblastoma (GBM), but only when the drug is delivered via catheter directly into the brain lesion, not after intravenous systemic delivery. The authors therefore explored alternative options of BZM delivery to the brain that would avoid invasive procedures and minimize systemic exposure.METHODSUsing mouse and rat GBM models, the authors applied intranasal drug delivery, where they co-administered BZM together with NEO100, a highly purified, GMP-manufactured version of perillyl alcohol that is used in clinical trials for intranasal therapy of GBM patients.RESULTSThe authors found that intranasal delivery of BZM combined with NEO100 significantly prolonged survival of tumor-bearing animals over those that received vehicle alone and also over those that received BZM alone or NEO100 alone. Moreover, BZM concentrations in the brain were higher after intranasal co-delivery with NEO100 as compared to delivery in the absence of NEO100.CONCLUSIONSThis study demonstrates that intranasal delivery with a NEO100-based formulation enables noninvasive, therapeutically effective brain delivery of a pharmaceutical agent that otherwise does not efficiently cross the BBB.

Abstract Glioblastoma is the most common malignant brain tumor. Efficient delivery of drugs targeting glioblastomas remains a challenge. Ephrin type-A receptor 3 (EPHA3) tyrosine kinase antibody-modified polylactide-co-glycolide (PLGA) nanoparticles (NPs) were developed to target glioblastoma via nose-to-brain delivery. Anti-EPHA3-modified, TBE-loaded NPs were prepared using an emulsion-solvent evaporation method, showed a sustained in vitro release profile up to 48 h and a mean particle size of 145.9 ± 8.7 nm. The cellular uptake of anti-EPHA3-modified NPs by C6 cells was significantly enhanced compared to that of nontargeting NPs (p < .01). In vivo imaging and distribution studies on the glioma-bearing rats showed that anti-EPHA3-modified NPs exhibited high fluorescence intensity in the brain and effectively accumulated to glioma tissues, indicating the targeting effect of anti-EPHA3. Glioma-bearing rats treated with anti-EPHA3-modified NPs resulted in significantly higher tumor cell apoptosis (p < .01) than that observed with other formulations and prolonged the median survival time of glioma-bearing rats to 26 days, which was 1.37-fold longer than that of PLGA NPs. The above results indicated that anti-EPHA3-modified NPs may potentially serve as a nose-to-brain drug carrier for the treatment of glioblastoma.

Glioblastoma multiforme (GBM) is a devastating primary tumor of the central nervous system with a significantly poor prognosis. The primary challenge in treating GBM lies in the restrictive nature of the blood-brain barrier (BBB), impeding effective drug delivery to the brain. In this study, intranasal polymeric micelles encapsulating a quercetin-etoposide combination were developed to induce synergistic apoptotic effects and enhance direct drug delivery to the brain. However, the in vivo anticancer efficacy of the unmodified micelle formulation via intranasal administration remains limited. Therefore, this aims to investigate the enhancement of the formulation by conjugating the micelles with a novel and highly potent cell-penetrating peptide (CPP), RMMR1, identified using the intra-dermal delivery technology platform developed by REMEDI Co., Ltd. This modification seeks to enhance the brain-targeting capability of the micelles. The CPP-modified micelles encapsulating the quercetin-etoposide combination (CM(QE)) demonstrated superior in vivo brain-delivery efficiency and enhanced cellular uptake after intranasal administration. Furthermore, animal studies showed significant tumor reduction and increased survival rates, with no significant changes in body weight observed. These findings suggest that intranasal administration of CM(QE) holds promise as a significant advancement in chemotherapy for GBM.

Glioma is recognized as the most infiltrative and lethal form of central nervous system tumors and is known for its limited response to standard therapeutic interventions, high recurrence rate, and unfavorable prognosis. Recent progress in gene and immunotherapy presents a renewed sense of optimism in the treatment of glioblastoma. However, the barriers to overcome include the blood-brain barrier (BBB) and the blood-brain tumor barrier (BBTB), as well as the suppressive immune microenvironment. Overcoming these barriers remains a significant challenge. Here, we developed a lipid nanoparticle platform incorporating a dual-functional peptide (cholesterol-DP7-ACP-T7-modified DOTAP or DAT-LNP) capable of targeting glioma across the BBB and BBTB for brain tumor immunotherapy. This system was designed to achieve two key functions. First, the system could effectively penetrate the BBB during accumulation within brain tissue following intravenous administration. Second, this system enhances the maturation of dendritic cells, the polarization of M1 macrophages, and the activation of cytotoxic CD8+ T cells. This multifaceted approach effectively mitigates the immunosuppressive tumor microenvironment of glioma and promotes robust antitumor immune responses. Overall, the intravenous administration of the delivery system designed in this study demonstrates significant therapeutic potential for glioma and holds promising applications in the field of cancer immunotherapy.

The blood-brain barrier (BBB) remains a formidable obstacle in medicine, preventing efficient penetration of chemotherapeutic and diagnostic agents to malignant gliomas. Here, we demonstrate that a transactivator of transcription (TAT) peptide-modified gold nanoparticle platform (TAT-Au NP) with a 5 nm core size is capable of crossing the BBB efficiently and delivering cargoes such as the anticancer drug doxorubicin (Dox) and Gd3+ contrast agents to brain tumor tissues. Treatment of mice bearing intracranial glioma xenografts with pH-sensitive Dox-conjugated TAT-Au NPs via a single intravenous administration leads to significant survival benefit when compared to the free Dox. Furthermore, we demonstrate that TAT-Au NPs are capable of delivering Gd3+ chelates for enhanced brain tumor imaging with a prolonged retention time of Gd3+ when compared to the free Gd3+ chelates. Collectively, these results show promising applications of the TAT-Au NPs for enhanced malignant brain tumor therapy and non-invasive imaging.

… glioma gene therapy lays on two important factors, the therapeutic genes and efficient delivery vehicles to cross the blood–brain barrier (BBB) and reach gliomas. In … /DNA nanoparticles (…

BACKGROUND AND OBJECTIVES Glioblastoma multiforme is considered as one of the most aggressive types of cancer, while various treatment techniques have been proposed. Magnetic nanoparticles (MNPs) loaded with drug and magnetically controlled and targeted to tissues affected by disease, is considered as a possible treatment. However, MNPs are difficult to penetrate the central nervous system and approach the unhealthy tissue, because of the blood-brain barrier (BBB). This study investigates numerically the delivery of magnetic nanoparticles through the barrier driven by normal pressure drop and external gradient magnetic fields, employing a simplified geometrical model, computational fluid dynamics and discrete element method. The goal of the study is to provide information regarding the permeability of the BBB under various conditions like the imposed forces and the shape of the domain, as a preliminary predictive tool. METHODS To achieve that, the three-dimensional Navier-Stokes equations are solved in the margin of a blood vessel along with a discrete model for the MNPs with various acting forces. The numerical results are compared with experimental measurements showing that the model can predict acceptably the flow behavior. RESULTS The effect of nanoparticles' size, external magnetic field and blood flow in the vessel, on the brain-barrier's permeability are investigated. Three different cases of available area among the endothelial cells per the MNPs' size ratio are also examined, showing that the MNPs' size and available area is not the dominant parameter affecting the permeability of the BBB. The results indicate that the applied magnetic field enhances the drug delivery into the central nervous system (CNS). When larger MNPs (∼100 nm) are exposed to an external magnetic field, the permeability can be improved up to 30%, while it is shown that smaller MNPs (∼10 nm) cannot be driven by the applied magnetic field and in this case the permeability remains relatively unchanged. Finally, the blood flow increase leads to a permeability improvement up to 15%. CONCLUSIONS The applied magnetic field improves up to 45% the permeability of the BBB for MNPs of 100 nm. The geometric characteristics of the endothelial cells, the nanoparticles' size and the blood flow are not so decisive parameters for the drug delivery into the CNS, compared to the external magnetic force.

Abstract The blood–brain barrier (BBB) and complex tumour immunosuppressive micro-environment posed austere challenges for combatting brain tumours such as the glioblastoma. In this study, we have developed a novel dual functional dendrimer drug delivery system (DDS) by the PAMAM and loaded with siLSINCT5 (NP- siRNA) for efficiently across the BBB to inhibit glioblastoma. To achieve the goal of BBB crossing, on the surface of NP-siRNA was decorated with the cell penetrating peptides tLyp-1 (tLypNP-siRNA). Moreover, to overcome the immunosuppressive microenvironment within the glioblastoma (GBM) tissues, a checkpoint inhibitor named as anti-NKG2A monoclonal antibody (aNKG2A), which was able of promoting anti-tumour immunity by unleashing both T and NK Cells, was further conjugated on the surface of siLSINCT5-loaded nanoparticles via the pH-sensitive linkage. Therefore, the developed dual functional and siLSINCT5-loaded dendrimer nanoparticles (tLyp/aNKNP-siRNA) was supposed to have the ability to efficiently cross the BBB and inhibit GBM by simultaneously inhibit the LSINCT5-activated signalling pathways and activate the anti-tumour immunity. The hypothesis was thoroughly confirmed by in vitro cellular and in vivo animal experiments, and provided a novel strategy for combating glioblastoma.

Tunneling nanotubes (TNTs) are thin, dynamic, long membrane protrusions that allow intercellular exchanges of signaling clues, molecules and organelles. The presence of TNTs and their involvement as drug delivery channels have been observed in several types of cancer, including glioblastoma. Recently, increased attention has been directed toward nanoparticles (NPs) that can be transported in TNTs. However, few data are available on the role of physical parameters of nanoparticles, such as size, shape, charge and flexibility, in determining their transfer efficiency between cells by TNTs. Here, we focused our attention on NP shape, manufacturing spherical, discoidal and deformable negatively charged lipid-based NPs with sizes <120 nm and similar stiffness. The TNT-mediated transfer of NPs was investigated in 2D and 3D culture models of human glioblastoma cells. The permeability and biocompatibility of the blood-brain barrier (BBB) were also assessed. Results showed that discoidal NPs displayed the highest TNT-mediated transfer efficiency between cancer cells, with a maximum velocity of 69 nm s-1, and a higher endothelial permeability (1.29 × 10-5 cm min-1) across the BBB in an in vitro model. This depends on the NP shape because discoidal NPs have a larger surface area exposed to the flow along the TNT channel. Overall, the results suggest that the shape of NPs is the game-changer for more efficient TNT-mediated transfer between cancer cells, thus introducing a sustainable solution to improve the diffusion rate at which the NPs spread in the tumour microenvironment, opening the possibility of ameliorating drug distribution to difficult-to-reach cancer cell populations.

Brain metabolism is uniquely regulated, and alterations in its metabolic networks often serve as critical drivers of the onset and progression of brain diseases. Therapeutic strategies that target these metabolic changes are regarded as fundamental to disease intervention. In complex metabolic networks, multi‐level metabolic dysregulation typically initiates a shared pathological process: the disruption of core cell metabolism leads to impaired cell–cell interactions, ultimately promoting the development of a malignant microenvironment that supports disease progression. This process encompasses complex mechanisms such as substance transport, cell signaling, and the dynamic regulation of the microenvironment. Smart nanodelivery systems, with their versatility, responsiveness, and modularity, can precisely modulate these dynamic metabolic networks in brain diseases, guided by the underlying pathological mechanisms. In this review, the metabolic network characteristics associated with brain diseases is summarized and the use of nanodelivery systems and their combinations are explored for metabolic regulation, aiming to establish a novel therapeutic paradigm.

… However, permeation across the blood–brain barrier (BBB), … known for their intratumoral heterogeneity and invasiveness, … Therefore, in this study, we evaluated active targeting strategy …

Abstract Alzheimer's disease (AD) remains a significant therapeutic challenge, primarily because the formidable blood‒brain barrier (BBB), which drastically limits the brain bioavailability of most drugs. Nanoparticle-based drug delivery systems offer a promising strategy to overcome this central obstacle. This review systematically examines the design, mechanisms, and applications of nanomedicine in AD therapy. We analyze key strategies for enhancing BBB penetration through surface engineering and the utilization of various nanocarriers, including liposomes, exosomes, dendrimers, and carbon dots. Furthermore, we discuss how stimuli-responsive release mechanisms (e.g. responsive to pH, enzymes, reactive oxygen species, light, or ultrasound) enable targeted and precise drug delivery. A critical focus is placed on how these multifunctional nanoplatforms can address multiple AD pathogenic pathways simultaneously, such as amyloid-β and tau aggregation, cholinergic dysfunction, oxidative stress, neuroinflammation, and gut‒brain axis dysregulation. Although preclinical evidence is compelling, the clinical translation of these nanotherapies is hindered by challenges related to long-term biocompatibility, scalable manufacturing, patient heterogeneity, and regulatory frameworks. This review highlights the translational potential of nanomedicine in AD treatment while outlining the key hurdles that must be addressed for its successful implementation.

… of K ATP channels and vWF in BTB vasculature but not on the … BTB vasculature that we activated with MS to increase BTB permeability without affecting the BBB permeability in glioma …

… Alterations in the BTB affect its permeability, and this structure … radiation necrosis associated with glioblastoma therapy 68 . As a … In this regard, ADCs with potent payloads or other stable …

Simple Summary The poor prognosis for glioblastoma (GBM) despite the existence of a standard-of-care treatment of resection, radiotherapy, and adjuvant chemotherapy has necessitated the exploration of other therapeutic avenues. One particularly promising avenue is an immunotherapeutic approach in which the body′s immune system is artificially stimulated to directly identify and attack the tumor cells. A variety of methods including immune checkpoint inhibition, T-cell transfer, vaccination, and a viral approach are being developed for GBM. Barriers such as tumor heterogeneity, the physical blood–brain barrier, the immunosuppressive nature of GBM, and the limited number of identifiable GBM-specific targets have reduced the efficacy of the aforementioned approaches. In the following review, we document the advances in immunotherapy, the barriers to implementation, and the development of a new technology (microbubble-enhanced focused ultrasound) to overcome the physical barriers to immunotherapy. Abstract Glioblastoma, or glioblastoma multiforme (GBM, WHO Grade IV), is a highly aggressive adult glioma. Despite extensive efforts to improve treatment, the current standard-of-care (SOC) regimen, which consists of maximal resection, radiotherapy, and temozolomide (TMZ), achieves only a 12–15 month survival. The clinical improvements achieved through immunotherapy in several extracranial solid tumors, including non-small-cell lung cancer, melanoma, and non-Hodgkin lymphoma, inspired investigations to pursue various immunotherapeutic interventions in adult glioblastoma patients. Despite some encouraging reports from preclinical and early-stage clinical trials, none of the tested agents have been convincing in Phase III clinical trials. One, but not the only, factor that is accountable for the slow progress is the blood–brain barrier, which prevents most antitumor drugs from reaching the target in appreciable amounts. Herein, we review the current state of immunotherapy in glioblastoma and discuss the significant challenges that prevent advancement. We also provide thoughts on steps that may be taken to remediate these challenges, including the application of ultrasound technologies.

Glioblastoma (GBM) is an extremely aggressive form of brain cancer that remains challenging to treat, especially owing to the lack of effective targeting and drug delivery concerns. Due to its anatomical advantages, the nose-to-brain strategy is an interesting route for drug delivery. Nanoengineering has provided technological tools and innovative strategies to overcome biotechnological limitations, which is promising for improving the effectiveness of conventional therapies. Herein, we designed a biomimetic multifunctional nanostructure produced by polymeric poly(d,l-lactic-co-glycolic) acid (PLGA) core loaded with Temozolomide (TMZ) coated with cell membrane isolated from glioma cancer cells. The developed nanostructures (NP-MB) were fully characterized, and their biological performance was investigated extensively. The results indicate that NP-MB could control TMZ release and promote TMZ permeation in the ex vivo nasal porcine mucosa. The higher cytotoxicity of NP-MB in different glioma cell lines, particularly against U251 cells, reinforces their potential for homotypic targeting. The chicken chorioallantoic membrane assay revealed a tumor size reduction and antiangiogenic activity. In vivo biodistribution studies showed that NP-MB effectively reaches the brain following nasal administration. These findings suggest that NP-MB holds promise as a biomimetic nanoplatform for effective targeting and homotypic recognition in GBM therapy with high potential for clinical translation.

Breast cancer brain metastases (BCBM) represent a major cause of morbidity and mortality among patients with breast cancer. Systemic drug therapy, which is usually effective against peripheral breast cancers, is often ineffective on BCBM due to its poor penetration through the blood-brain tumor barrier (BTB). In this study, prostate-specific membrane antigen (PSMA) with internalization function was found to be specifically up-regulated on BCBM-associated BTB while barely detectable in normal blood-brain barrier (BBB). Here, a nanotechnology approach is reported that can overcome the BTB through ACUPA (A) and cyclic TT1 (cT) co-functionalized nanoparticles (A-NPs-cT). A-NPs-cT selectively target PSMA on BTB for specific BTB crossing and specially bind with p32 for BCBM targeting. We disclosed the effectual synergism of doxorubicin (DOX) and lapatinib (LAP) for BCBM combined therapy. A-NPs-cT exhibited boosted uptake than integrin-targeting RGD-modified NPs in BTB endothelial cells and displayed about 4.57-fold stronger penetration through the BCBM-associated BTB as compared to the normal BBB. In vivo studies showed specific BTB crossing, and remission of BCBM and prolonged survival with DOX and LAP combinatorial regimen. A-NPs-cT based DOX and LAP innovative combined therapy envisioned improved therapeutic intervention for clinical management of BCBM, for which surgery is generally inapplicable and insufficient.