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Multimodal Mechano-adaptive Artificial Synovial Fluid Drives In-Situ Engineering of Anti-Pyroptotic Extracellular Vesicles to Arrest Preclinical Osteoarthritis

ABSTRACT: Effective early interventions for knee protection in exercise enthusiasts and pre-clinical symptomatic knee osteoarthritis (OA) patients are lacking. Abnormal mechanical loading initiates a dual pyroptotic loop between chondrocytes and macrophages, converting healthy cartilage to pathology. Herein, we engineered a multifunctional artificial synovial fluid, pPBA@MN UM6@Co (PMUC), to deliver graded protection and repair of early pathogenetic cartilage. Intra articular PMUC builds a persistent hydration layer via water bonding, mimicking native synovial fluid, markedly enhancing lubrication and dissipating mechanical stress. When abnormal stress provokes ultra early cartilage lesions, the ensuing ROS (·OH) surge cleaves boronate esters and glycosidic bonds in PMUC, releasing mannose (Man) and UM6@Co (UC) nanocomplexes. Activation of the hexosamine biosynthetic pathway (HBP) suppresses Caspase-3–GSDME-mediated pyroptosis in chondrocytes while promoting in situ formation and engineering of extracellular vesicle (EV) derived from resident and synovial macrophages. These EVs, functioning as intercellular messengers within the articular cavity, collectively disrupt the chondrocyte-macrophage pyroptosis loop and facilitate matrix regeneration. In high-load exercise and early OA rat models, PMUC prevented further erosion and healed existing defects, achieving full cartilage regeneration and restored locomotor performance within eight weeks. By coupling adaptive lubrication with stress triggered immune-metabolic modulation, PMUC offers the first stage specific strategy that simultaneously protects healthy joints and repairs silent OA, filling a critical clinical gap for exercise enthusiasts and early-stage patients.

ORGANISM(S): Mus musculus

PROVIDER: GSE314982 | GEO | 2026/08/04

REPOSITORIES: GEO

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Project description:Background: Managing early-to-mid-stage knee osteoarthritis (OA) remains an unmet clinical need. Synovitis drives OA progression, but current anti-inflammatory therapies offer limited efficacy. Disrupted fibroblast lineage homeostasis is central in chronic inflammation, and targeting this may attenuate synovitis and pathological synovium-cartilage crosstalk in knee OA. Methods: Synovial single-cell sequencing, clinical histological and transcriptomic data assessed fibroblast lineage changes and similarities between dermal fibroblasts (DFb) and synovial fibroblasts. Labeled DFb injection in rat knees evaluated cell retention. Rat anterior cruciate ligament transection (ACLT) model with intra-articular DFb injection assessed the therapeutic efficacy. Co-cultures characterized DFb paracrine effects on synovial fibroblasts and chondrocytes. Proteomics identified active components in DFb supernatants. Results: OA synovium exhibits disrupted fibroblast lineage homeostasis, marked by a prominent pro-inflammatory phenotype in synovial fibroblasts. DFb show high transcriptomic and morphological similarity to synovial fibroblasts from healthy donors. Post-injection, DFb engrafted within the synovium with more than 3-week retention. Intra-articular DFb injection alleviated synovitis and cartilage degeneration in ACLT-induced OA rats. Co-cultures confirmed DFb alleviated cytokine-induced inflammatory responses in synovial fibroblasts and chondrocytes via paracrine mechanisms, and integrated proteomic/transcriptomic analyses identified apolipoprotein D (APOD) as a potential key mediator of these anti-inflammatory effects. Conclusions: This study validates a novel cell therapy for OA that targets disrupted fibroblast lineage homeostasis in synovitis. By modulating pro-inflammatory synovial fibroblasts and alleviating synovitis through restoring lineage homeostasis, DFb ameliorate OA progression, providing a new theoretical basis and practical approach for OA cell therapy research.

Project description:Autologous chondrocyte transplantation (ACT) is a routine technique to regenerate focal cartilage lesions. However, patients with osteoarthritis (OA) are lacking an appropriate long-lasting treatment alternative, partly since it is not known if chondrocytes from OA patients have the same chondrogenic differentiation potential as chondrocytes from donors not affected by OA. Articular chondrocytes from patients with OA undergoing total knee replacement (Mankin Score >3, AhlbÃ¤ck Score >2) and from patients undergoing ACT, here referred to as normal donors (ND), were isolated applying protocols used for ACT. Their chondrogenic differentiation potential was evaluated both in high-density pellet and scaffold (Hyaff-11) cultures by histological proteoglycan assessment (Bern Score) and immunohistochemistry for collagen types I and II. Chondrocytes cultured in monolayer and scaffolds were subjected to gene expression profiling using genome-wide oligonucleotide microarrays. Expression data were verified by using quantitative RT-PCR. Chondrocytes from ND and OA donors demonstrated accumulation of comparable amounts of cartilage matrix components, including sulphated proteoglycans and collagen types I and II. The mRNA expression of cartilage markers (COL2A1, COMP, aggrecan, CRTL1, SOX9) and genes involved in matrix synthesis (biglycan, COL9A2, COL11A1, TIMP4, CILP2) was highly induced in 3D cultures of chondrocytes from both donor groups. Genes associated with hypertrophic or OA cartilage (COL10A1, RUNX2, periostin, ALP, PTHR1, MMP13, COL1A1, COL3A1) were not significantly regulated between the two groups of donors. The expression of 661 genes, including COMP, FN1, and SOX9, were differentially regulated between OA and ND chondrocytes cultured in monolayer. During scaffold culture, the differences diminished between the OA and ND chondrocytes, and only 184 genes were differentially regulated. Only few genes were differentially expressed between OA and ND chondrocytes in Hyaff-11 culture. The risk of differentiation into hypertrophic cartilage does not seem to be increased for OA chondrocytes. Our findings suggest that the chondrogenic capacity is not significantly affected by OA and OA chondrocytes fulfill the requirements for matrix-associated ACT. Experiment Overall Design: Gene expression profiles of monolayer cultures (ML; passage 2) and Hyaff-11 scaffold cultures (3D; 14 days in vitro) of chondrocytes from 3 normal donors (ND; underwent ACT treatment) and 3 donors suffering from Osteoarthritis (OA; underwent knee replacement surgery) were determined. Comparative analyses between 3D and ML cultures (3D vs. ML) were performed to assess differentiation capacity of ND and OA chondrocytes. Furthermore, OA-related differences were determined comparing OA and ND monolayers as well as scaffold cultures (each OA vs. ND).

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Multimodal Mechano-adaptive Artificial Synovial Fluid Drives In-Situ Engineering of Anti-Pyroptotic Extracellular Vesicles to Arrest Preclinical Osteoarthritis

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