尿酸晶体消除研究的原创基础性研究或综述（1区）

The accumulation of monosodium urate (MSU) crystals in joints plays a central role in the pathogenesis of gouty arthritis. While conventional treatments for acute gout focus on symptom relief, they do not address the root cause-crystal deposition. Recombinant uricase offers a promising long-term solution by catalyzing the conversion of poorly soluble uric acid into highly soluble allantoin, facilitating MSU crystal clearance. In this study, we developed a novel assay system using acridine orange (AO)-doped MSU crystals as a solid substrate and real-time sensing unit to monitor uricase activity under physiological conditions. The MSU-AO crystals were comprehensively characterized by spectroscopic, microscopic, and diffraction-based techniques. Uricase activity under physiological conditions was monitored by two complementary readouts: fluorescence emission from AO released during crystal dissolution, and microscopic measurement of crystal size reduction. Both outputs exhibited strong linear correlations with enzyme concentration, demonstrating the potential of this system as a platform for therapeutic uricase evaluation. Importantly, the microscopic assay required only 2 µL of sample and was successfully applied to rat serum and porcine synovial fluid, highlighting its suitability for use with limited quantities of biological specimens.

The increased utilization of titanium dioxide (TiO2) nanoparticles (TNPs) in various industrial and consumer products has raised concerns regarding its harmful effect due to its accumulation within the different systems of the human body. Here, we focused on the influence of TNPs on the growth and aggregation of two crucial crystalline substances, calcium phosphate (CaP) and monosodium urate (MSU), particularly its implications in gout disease. In this study, we adopted microscopic techniques and generated kinetic models to examine the interactions between TNPs, CaP and MSU, and crystallization, under controlled laboratory conditions. Our findings reveal that TNPs not only facilitate the growth of these crystals but also promote their co-aggregations. Crystal dissolution kinetics also exhibit that an increase in TNPs concentration corresponds to a reduction in the dissolution rate of CaP and MSU crystals in presence of the dissoluting agent hydroxycitrate (Hcit). These observations suggest that TNPs can stabilize CaP+MSU mixed crystals, which underscores the significance of TNPs’ exposure in the pathogenesis of gout disease.

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Tophi, inflammatory granulomas formed by intra-articular monosodium urate (MSU) crystal deposition, remain challenging due to limited drug efficacy. While arthroscopic surgery removes tophi rapidly, mechanical debridement risks injury, and intraoperative MSU release can trigger severe oxidative stress induced inflammatory storm. To overcome this, we developed a cascade nanozyme, Ce-MOF@Pt, enabling synergistic MSU clearance and ROS scavenging for MSU-induced gouty arthritis. Pt nanoparticles possess oxidase (OXD)-like activity, dissolving deeply embedded MSU crystals without mechanical injury and incidentally producing anti-inflammatory allantoin. The Ce-MOF matrix supports Pt and duplicates catalase (CAT)/superoxide dismutase (SOD)-like activities, cascading H2O2 decomposition and MSU-induced ROS elimination. As UA degradation elevates the local pH values, its dominant activity intelligently switches from OXD-like to SOD-like mode, while the CAT-like activity remains consistently high, ensuring continuous clearance of the H2O2 byproduct and offering integrated anti-oxidative therapy. In vitro, Ce-MOF@Pt reduced inflammation via ROS scavenging and macrophage reprogramming. In vivo, it alleviated pain symptoms and joint inflammation in MSU-induced gouty arthritis mice. Transcriptomics revealed Ce-MOF@Pt mitigated the inflammatory storm by alleviating endoplasmic reticulum stress. This novel Ce-MOF@Pt strategy offers minimally invasive tophi dissolution and prevents MSU-induced inflammation, providing a promising therapeutic approach for tophi.

The core to the treatment of gout is the elimination of pathologic crystal, monosodium urate monohydrate (MSUM). The primary treatment available is to gradually dissolve the "culprit crystals" by lowering the blood uric acid concentration with medications, which often takes a long time and in severe cases must still be treated surgically. Herein, we developed a dynamic bionic platform based on a hydrogel composite membrane (HCM) to screen the direct facilitated solubilization of MSUM crystals by small organic molecules in bionic saturated, or even supersaturated, solutions. The customized and biologically safe (NAGA/PEGDA/NIPAM) HCM, which is consistent with the main amino acid composition of articular cartilage, well mimics the entire process of organic molecules leading to the dissolution of MSUM crystals in the joint system. With the verifications of this platform, it is shown that l-aspartic acid (ASP) significantly promotes the dissolution of MSUM crystals not only in saturated but also in supersaturated solutions. Furthermore, a novel mechanism called "crane effect" was used to explain this "dissolution effect" of ASP on MSUM, which stems from the ability of ASP to lock onto the surface of MSUM crystals through hydrogen bonding by virtue of its two carboxyl groups, and simultaneously its amino group lifts the uric acid molecules from the surface of MSUM crystals by virtue of interactions of hydrogen bonding. The results of bulk crystallization, scanning electron microscopy (SEM), powder X-diffraction (PXRD), and density-functional theory (DFT) studies are quantitatively consistent with this hypothetical "crane effect" mechanism. Hence, this HCM-based functional platform could provide entirely novel ideas and methods for drug design and screening for the treatment of pathological crystal diseases of gout.

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Objective To investigate the potential role of lymphatic system in gouty arthritis (GA) by integrating clinical observations in human draining lymph nodes with functional studies in a mouse model. Methods We first conducted ultrasound examinations of draining lymph nodes in 30 GA patients and 30 healthy controls. Subsequently, we established mouse models of acute and chronic GA via monosodium urate (MSU) crystal injection. Lymphatic nodes were assessed using ultrasound, the structure and function of lymphatic vessels were assessed using histology and near-infrared imaging. We further employed a VEGFR-3 inhibitor to disrupt lymphatic function and evaluated its impact on inflammatory resolution in MSU-induced GA mouse model. Results Patients with GA showed significantly larger draining lymph nodes compared with healthy controls, a finding also observed in MSU-induced GA mouse model. The concentration of uric acid in the draining lymph nodes after MSU injection was significantly elevated and exceeded that in the serum. The structure of lymphatic vessels in paw tissues was impaired, and the draining function was reduced during the inflammatory process induced by MSU injection at 1 and 4 weeks. Lymphatic vessel leakage was observed after 4 weeks of MSU treatment. Critically, pharmacological inhibition of VEGFR-3, which disrupted lymphatic integrity, subsequently delayed the resolution of MSU-induced inflammation. Conclusion Our findings in humans demonstrate a clinical association between GA and lymphatic system engagement. Mouse studies highlight a dual and critical role of the lymphatic system in GA pathogenesis: it is involved in clearance but vulnerable to damage, which may perpetuate inflammation.

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Introduction Efficient and complete debridement of intra-articular deposits of monosodium urate crystals is rarely achieved by existing arthroscopic tools such as shavers or radiofrequency ablation, while cavitation technology represents a prospective solution for the non-invasive clearance of adhesions at intra-articular interfaces. Methods Simulation modeling was conducted to identify the optimal parameters for the device, including nozzle diameters and jet pressures. Gouty arthritis model was established in twelve rats that were equally and randomly allocated into a cavitation debridement group or a curette debridement group. A direct injection nozzle was designed and then applied on animal model to verify the effect of the cavitation jet device on the removal of crystal deposits. Image analysis was performed to evaluate the clearance efficiency of the cavitation device and the pathological features of surrounding tissue were collected in all groups. Results To maximize cavitation with the practical requirements of the operation, an experimental rig was applied, including a 1 mm direct injection nozzle with a jet pressure of 2.0 MPa at a distance of 20 mm and a nitrogen bottle as high-pressure gas source. With regards to feasibility of the device, the clearance rates in the cavitation group were over 97% and were significantly different from the control group. Pathological examination showed that the deposition of monosodium urate crystals was removed completely while preserving the normal structure of the collagen fibers. Conclusions We developed a promising surgical device to efficiently remove intra-articular deposits of monosodium urate crystals. The feasibility and safety profile of the device were also verified in a rat model. Our findings provide a non-invasive method for the intraoperative treatment of refractory gouty arthritis.

Resolution of inflammation is essential for tissue homeostasis and represents a promising approach to inflammatory disorders. Here we found that developmental endothelial locus-1 (DEL-1), a secreted protein that inhibits leukocyte–endothelial adhesion and inflammation initiation, also functions as a non-redundant downstream effector in inflammation clearance. In human and mouse periodontitis, waning of inflammation was correlated with DEL-1 upregulation, whereas resolution of experimental periodontitis failed in DEL-1 deficiency. This concept was mechanistically substantiated in acute monosodium-urate-crystal-induced inflammation, where the pro-resolution function of DEL-1 was attributed to effective apoptotic neutrophil clearance (efferocytosis). DEL-1-mediated efferocytosis induced liver X receptor–dependent macrophage reprogramming to a pro-resolving phenotype and was required for optimal production of at least certain specific pro-resolving mediators. Experiments in transgenic mice with cell-specific overexpression of DEL-1 linked its anti-leukocyte-recruitment action to endothelial cell–derived DEL-1 and its efferocytic/pro-resolving action to macrophage-derived DEL-1. Thus, the compartmentalized expression of DEL-1 facilitates distinct homeostatic functions in an appropriate context that can be harnessed therapeutically. DEL-1 protein interferes with leukocyte adhesion to prevent inflammation. Chavakis and colleagues now show that DEL-1 contributes to tissue resolution after inflammation by promoting macrophage-mediated efferocytosis and M2-like pro-resolving activities.

Gout is a systemic metabolic inflammatory disease driven by hyperuricemia and monosodium urate crystal deposition, and is frequently accompanied by chronic kidney disease and uric acid nephrolithiasis. Current evidence indicates that acidic urine, hypocitraturia, and insufficient ammonium excretion are common in gout patients, and may be associated with insulin resistance, impaired renal ammoniagenesis, and abnormalities in tubular acid-base regulation. Persistent urinary acidification may contribute to the development and progression of uric acid stone formation and gout-related renal injury by reducing uric acid solubility, promoting crystal formation and intratubular deposition, and decreasing renal uric acid clearance. Urinary alkalization therapy can increase urine pH, thereby enhancing uric acid solubility and excretion, and has shown potential in some studies to improve serum urate levels, proteinuria, renal function parameters, and gout flare frequency, especially when using citrate-based alkali. However, the currently available evidence is mainly derived from observational studies and small prospective investigations, and recommendations across international guidelines remain inconsistent. High-quality evidence is still lacking regarding the optimal target population, urine pH range, choice of alkalizing agents, monitoring strategies, and long-term efficacy. Well-designed prospective studies are therefore needed to clarify the clinical role of urinary alkalization in renal protection among patients with gout.

Hyperuricemia and its complications, including gouty arthritis and hyperuricemic nephropathy, are driven by elevated serum urate levels and crystal deposition. While exogenous uricase offers therapeutic potential, its utility is limited by rapid clearance and immunogenicity. Here we show a malic acid-derived lipid nanoparticle platform with antioxidant and low-immunogenicity properties for delivering circular RNA encoding secretory uricase to treat hyperuricemia and its complications. Leveraging the safety and anti-inflammatory and antioxidant properties of malic acid, a combinatorial library of ionizable lipids is developed. After systematic screening and optimization, LMA2-C10 LNPs are selected to deliver circRNA for its high transfection efficiency, low-immunogenicity, and antioxidant activity. In male animal models, the system achieves sustained urate reduction, attenuation of tissue inflammation and fibrosis, alleviation of arthritic pain, and preservation of renal function. This integrated strategy simultaneously addresses hepatic urate catabolism, peripheral crystal clearance, and long-lasting pharmacological activity, presenting an alternative strategy to resolve the core challenges in hyperuricemia management. Antioxidant malic-acid-derived lipid nanoparticles deliver circRNA encoding secretory uricase, showing long-lasting urate reduction, peripheral crystal clearance, reduced inflammation and fibrosis, and preserved renal function in hyperuricemia models.

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Background: Gout is based on the deposition of monosodium urate (MSU) crystals. While it is well established that life-style intervention and/or conventional urate lowering therapy can lead to a decrease in serum urate levels, the impact of such interventions to resolve already existing MSU deposits is very limited. Objectives: In this study we wanted to determine if and to what extent MSU deposits resolve if patients follow structured life-style intervention or continuously conventional urate lowering therapy. Methods: Subjects with diagnosis of gout and the presence of MSU deposits in the feet in baseline dual energy CT (DECT) scan, received either life-style intervention only (N=24) or additional conventional urate lowering therapy (allopurinol: N=29, febuxostat: N=22, benzbromarone N=2) for a mean period of 18 months before receiving a follow-up DECT examination. MSU deposits were quantified by volumetric measurement and semi quantitative scoring at baseline and follow up. Results: Serum uric acid (SUA) level decreased from 7.2±1.7 to 6.7±1.7mg/dl with life-style intervention; from 7.0±1.5 to 5.5±1.8mg/dl with allopurinol and from7.8±3.0 to 5.1 ± 2.5mg/dl with febuxostat. MSU volume significantly decreased in patients undergoing life-style intervention (baseline: 0,07cm3 ± 0,09; follow up: 0,05 ± 0,15cm3; p=0.007), treatment with allopurinol (0,11 ± 0.15 cm3 to follow up: 0.02 ± 0,04 cm3, p<0.001) or febuxostat (MSU volume baseline: 0.99 ± 2.8 to follow up: 0.64 ± 2.09; p=0.001). With respect to conversion from a DECT+ into a DECT- state, baseline MSU deposit burden, but not baseline SUA level or decrease in SUA level, was associated with reaching a DECT- state. Thus patients with smaller deposits were more likely to completely resolve the deposits. Conclusion: We show that both life-style intervention and conventional urate lowering drug therapy reduce the volume of monosodium urate deposits. The size of MSU deposits, but not serum urate level, was the main factor that influenced complete resolution of deposits. This finding reemphasizes that the burden of deposits essentially defines the likelihood and time for complete resolution of gout. References [1] Manger B, Lell M, Wacker J, Schett G, Rech J. Detection of periarticular urate deposits with dual energy CT in patients with acute gouty arthritis. Ann Rheum Dis. 2012;71(3):470-2. [2] Bongartz T, Glazebrook KN, Kavros SJ, Murthy NS, Merry SP, Franz WB, 3rd, et al. Dual-energy CT for the diagnosis of gout: an accuracy and diagnostic yield study. Ann Rheum Dis. 2015;74(6):1072-7. [3] Bayat S, Aati O, Rech J, Sapsford M, Cavallaro A, Lell M, et al. Development of a Dual-Energy Computed Tomography Scoring System for Measurement of Urate Deposition in Gout. Arthritis Care Res (Hoboken). 2016;68(6):769-75. Disclosure of Interests: Sara Bayat: None declared, Hanna Ellmann: None declared, Elizabeth Araujo: None declared, Bernhard Manger: None declared, Melanie Hagen: None declared, Arnd Kleyer Grant/research support from: Lilly, Consultant for: Lilly, Speakers bureau: Abbvie, Alexandeer Cavallaro: None declared, Michael Lell: None declared, Hannah Schenker : None declared, David Simon Grant/research support from: Novartis, Consultant for: Lilly, Speakers bureau: Janssen, Koray Tascilar: None declared, Herbert S.B. Baraf: None declared, Georg Schett: None declared, Jürgen Rech Grant/research support from: Bristol-Myers Squibb and Celgene (greater than $10,000), Consultant for: Bristol-Myers Squibb, Celgene, Chugai, GlaxoSmithKline, Janssen, Eli Lilly, Novartis, Roche, Sanofi Aventis, and UCB (in total more than $10,000), Speakers bureau: Bristol-Myers Squibb, Celgene, Chugai, GlaxoSmithKline, Janssen, Eli Lilly, Novartis, Roche, Sanofi Aventis, and UCB (in total more than $10,000)

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Acute gout, characterized by recurrent inflammatory flares caused by monosodium urate (MSU) crystal deposition, presents a therapeutic challenge due to the limited efficacy of current drugs in concurrently eliminating MSU crystals and resolving inflammation. To overcome this, a manganese‐based nanozyme derived from a ZIF‐8 metal‐organic framework (MOF) is developed, which is designed to avoid the reliance on precious metals seen in existing urate oxidase‐mimetic systems. By leveraging competitive coordination between zinc and manganese during MOF synthesis, atomic‐level dispersion of manganese active sites with precise modulation of the Mn4+/Mn2+ redox equilibrium is achieved. Coupled with optimized pyrrolic/graphitic nitrogen configurations, the nanozyme demonstrates triple enzymatic activities: urate oxidase‐like activity for uric acid degradation (preventing MSU crystallization), catalase‐like activity for H2O2 scavenging, and superoxide dismutase‐like activity to alleviate oxidative stress. Notably, the nanozyme directly destabilizes preformed MSU crystals via surface charge modulation and lattice disruption. In an acute gout model, the nanozyme surpasses colchicine in accelerating MSU clearance—through simultaneous dissolution of existing crystals and inhibition of new formation—while reducing inflammatory cytokine levels without systemic toxicity. This work introduces a redox‐adaptive nanozyme design strategy for managing crystalopathies, providing a dual‐action solution to combat both MSU‐driven inflammation and crystallization.

This review describes the three broad stages of acute inflammation in the context of gout: initiation, leucocyte mobilization, and self‐resolution. A typical case of a gout flare is presented. The role of the NLRP3 inflammasome in acute monosodium urate crystal–induced inflammation is reviewed in detail. Treatment strategies for gout are outlined in the context of the mechanisms of NLRP3 inflammasome–mediated acute inflammation.

Gout is a crystal-associated autoinflammatory disease triggered by monosodium urate (MSU) crystals, clinically characterized by recurrent transitions between acute inflammatory flares dominated by innate immunity and a state of “trained immunity” during the remission phase. However, previous studies have mostly focused on single time points or local lesions. Such approaches fail to systematically explain the recurrent nature of acute gout flares and the mechanisms underlying multi−system involvement. By integrating evidence from single-cell and spatial transcriptomics as well as mechanistic investigations, this review systematically summarizes the immunopathological features of gout within a spatiotemporal immune framework. At the temporal level, acute gout flares are driven by innate immune activation of the NOD-like receptor pyrin domain-containing protein 3 (NLRP3)–interleukin-1β (IL-1β) inflammatory cascade. The inflammation then undergoes self-limited resolution mediated by regulatory T cells (Tregs), M2-polarized macrophages, aggregated neutrophil extracellular traps (aggNETs), and pro-resolving lipid mediators. persistent low-grade activation of monocytes/macrophages can still be observed, sustaining a state of “trained immunity.” At the spatial level, integrated evidence indicates an immune gradient across the joint, bone, and circulation, ranging from focal hyper-inflammation to systemic low-grade activation. Based on these findings, we propose a time-window stratified intervention strategy centered on the NLRP3–IL-1β axis, and identify inflammatory markers in the joints, subchondral bone, and peripheral blood as the basis for spatially targeted stratification. These insights provide novel perspectives for shifting gout management from the control of individual flares to recurrence risk management and personalized therapy.

The deformities and disabilities resulting from bone destruction in gouty arthritis impose substantial physical and psychological burdens on patients, underscoring the urgent need to elucidate the mechanisms underlying gout-induced osteolysis. Monosodium urate (MSU) crystals play a central role in the pathogenesis of bone destruction in gouty arthritis, significantly disrupting the activity and function of bone-related cells. Mechanistically, MSU induces bone loss by triggering oxidative stress, amplifying inflammatory cascades, and dysregulating bone remodeling pathways. Understanding these pathological mechanisms is essential for early clinical intervention and the development of targeted therapies to prevent disease progression. The present review systematically examines the multifaceted impact of MSU on bone homeostasis and its molecular interactions in gouty arthritis-associated bone destruction, providing insights to refine diagnostic strategies and advance novel therapeutic approaches.

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Urate-lowering therapies for the management of gout lead to a reduction in serum urate levels, monosodium urate crystal deposition, and the clinical features of gout, including painful and disabling gout flares, chronic gouty arthritis, and tophi. Thus, disease remission is a potential goal of urate-lowering therapy. In 2016, preliminary gout remission criteria were developed by a large group of rheumatologists and researchers with expertise in gout. The preliminary gout remission criteria were defined as: serum urate < 0.36 mmol/L (6 mg/dL); an absence of gout flares; an absence of tophi; pain due to gout < 2 on a 0–10 scale; and a patient global assessment < 2 on a 0–10 scale over a 12-month period. In this critical review, we describe the development of the preliminary gout remission criteria, the properties of the preliminary gout remission criteria, and clinical studies of gout remission in people taking urate-lowering therapy. We also describe a future research agenda for gout remission.

This study aims to compare different methods of monosodium urate crystal (MSU) detection in synovial fluid (SF) and the effect of sample storage and handling on crystal detection. A systematic literature search was performed in MEDLINE, EMBASE, the Cochrane Library and the American College of Rheumatology/European League Against Rheumatism conference abstracts of 2010 and 2011. Studies that compared a method for detecting MSU crystals in SF with polarised light microscopy (PLM) or compared various SF storage and handling factors with the detection of MSU crystals as an outcome were included. Twelve studies out of 247 identified references were included in the review. Seven studies compared different methods of MSU crystal detection in SF with PLM. Due to study heterogeneity, methodological limitations and risk of bias, no firm conclusions could be drawn from the available data. Five studies examining SF storage and handling factors were identified. A reduction in MSU crystal concentration was observed over time at room temperature that was not seen in refrigerated samples. The use of anticoagulation as a storage medium provided no benefit. Dried cytospin preparations appeared to be a suitable medium for long-term storage and delayed crystal analysis for at least 12 months. The existing data do not provide a compelling argument for the replacement of PLM as the current standard. SF sample storage and handling have an effect on MSU crystals and may impact on the reliability of analysis.

BACKGROUND Gouty arthritis is a complex form of inflammatory arthritis, triggered by the sedimentation of monosodium urate crystals in periarticular tissues, synovial joints, and other sites in the body. Curcumin is a natural polyphenol compound, isolated from the rhizome of the plant Curcuma longa, possessing countless physiological features, including antioxidant, anti-inflammatory, and anti-rheumatic qualities. OBJECTIVE This study aimed to discuss the beneficial impacts of curcumin and its mechanism in treating gout disease. METHODS Ten English and Persian databases were used to conduct a thorough literature search. Studies examining the anti-gouty arthritis effects of curcumin and meeting the inclusion criteria were included. RESULTS According to the studies, curcumin has shown xanthine oxidase and urate transporter-1 inhibitory properties, uric acid inhibitory characteristics, and antioxidant and anti-inflammatory effects. However, some articles found no prominent reduction in uric acid levels. CONCLUSION In this review, we emphasized the potency of curcumin and its compounds against gouty arthritis. Despite the potency, we suggest an additional well-designed evaluation of curcumin, before its therapeutic effectiveness is completely approved as an anti-gouty arthritis agent.

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Spatiotemporal regulation of therapeutic enzymes is desirable for enhancing the efficacy and safety of enzyme-based treatments for metabolic diseases, yet the absence of techniques capable of on-demand manipulating the in vivo catalytic activity of urate oxidase (UOx) represents a significant challenge in achieving precise gout therapy. Herein, we report a cyclic cascade nanohybrid urate oxidase (NUOx) comprised of a Fe3O4 nanoring core and a UOx shell, whose activity can be switched on and off on-demand using a deep-penetrated alternating magnetic field (AMF). The Fe3O4 nanoring under AMF exposure functions as a nanoheater to stimulate its intrinsic catalase (CAT) activity for oxygen recycling, which in turn activates UOx/CAT cascade for controlled uric acid degradation. Through the synergistic magnetothermal and UOx/CAT cyclic cascade, NUOx exhibited greatly enhanced AMF-tunability with an ON/OFF ratio as high as 7.6 and robust reversibility. This magnetically switchable NUOx enabled dynamic control of uric acid homeostasis without inducing hypouricemia and more efficient dissolution of monosodium urate crystals in vitro. In vivo experiments in a rat model of acute gout arthritis demonstrated that intra-articular administrated NUOx combined with AMF can more effectively relieve joint hypoxia, reduce uric acid levels and suppress joint inflammation, leading to a magneto-catalytic therapy with tunable therapeutic potential to enhance efficacy while minimizing potential side effects in gout treatment. These findings provide new insights into the development of nanohybrid enzymes with robust magnetic responsiveness for metabolic reprogramming and disease treatment.

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