NLRP3 Inflammasome and Extracellular Vesicles in Knee Osteoarthritis: Molecular Mechanisms, Biomarkers, and Translational Therapeutic Strategies

Background/Objectives: Osteoarthritis (OA) is the most prevalent degenerative joint disease worldwide, characterized by progressive cartilage degeneration, chronic synovial inflammation, and abnormal subchondral bone remodeling, with high disability rates and a substantial disease burden. The knee joint is the most commonly affected site in OA; therefore, this review focuses on knee OA. Traditionally, knee OA has been regarded as cartilage degeneration caused solely by mechanical wear; however, accumulating preclinical and translational evidence supports NLR family pyrin domain-containing protein 3 (NLRP3) inflammasome activation as an important contributing factor in specific inflammatory and metabolic knee OA phenotypes. This review aims to integrate the potential roles of the NLRP3 inflammasome and extracellular vesicles (EVs) in knee OA, and to explore their exploratory biomarker value and investigational therapeutic potential. Methods: This narrative review synthesizes the current published knowledge regarding NLRP3 inflammasome biology, knee OA pathogenesis, and translational research on extracellular-vesicle-based diagnostics and therapeutics. The relevant peer-reviewed literature was identified via literature searches in major biomedical databases up to September 2026. The authors assembled references based on thematic fit to the review scope, study quality, and maturity of available evidence. Original reports, clinical trials, meta-analyses, published systematic reviews, and clinical guidelines were considered; the non-peer-reviewed grey literature was not used as primary supporting evidence. Where conflicting study outcomes exist in the published literature, human clinical data and randomized controlled trial evidence were given greater interpretive weight relative to preclinical in vitro and animal-model findings. Results: This review proposes that the coupling among inflammatory responses, pyroptosis, and EVs-mediated signal transmission may constitute an important pathological link in knee OA progression. NLRP3 integrates mechanical, metabolic, and aging signals in chondrocytes, synovial macrophages, and subchondral bone cells, triggering pyroptosis and matrix degradation; it also mediates transcellular and trans-tissue cascade amplification of inflammatory signals via EVs and may drive the progression from focal injury to pan-articular degeneration. Small-molecule inhibitors targeting NLRP3 have evolved from the early experimental probe MCC950 to a new generation of tissue-selective clinical candidates; however, no NLRP3 inhibitor has yet entered dedicated clinical trials for knee OA. NLRP3-pathway molecules associated with EVs have exploratory potential as liquid biopsy biomarkers reflecting local joint inflammatory burden and may be investigated for early diagnosis and patient stratification in knee OA; engineered EVs may serve as targeted delivery vehicles, and preclinical studies have demonstrated inflammatory-microenvironment-responsive NLRP3 inhibition and cartilage-specific enrichment. Conclusions: NLRP3-targeted intervention is an investigational strategy with potential disease-modifying intent in knee OA, but it remains at the preclinical and early translational stages. To date, no clinical evidence demonstrates that selective NLRP3 inhibition improves pain, function, structural progression, or other patient-centered outcomes in knee OA; therefore, disease modification by NLRP3 inhibition remains unproven. Its early translational research faces core bottlenecks, including long-term local medication safety, intra-articular delivery efficiency, the high heterogeneity of knee OA, and standardized quality control of vesicle products. Future efforts should focus on vesicle-based multi-omics inflammatory subtyping, engineered vesicle systems that combine deep cartilage penetration with long-term joint retention, and multi-mechanism combination therapies. These approaches may generate hypotheses for future research into whether knee OA treatment can eventually move beyond symptomatic relief toward disease modification; however, this transition remains unproven and requires dedicated clinical trials with appropriate clinical endpoints. It should also be acknowledged that the available evidence is not entirely consistent: some studies have failed to demonstrate that stress-induced cartilage degradation is NLRP3-dependent, underscoring the importance of OA heterogeneity. Current evidence is largely derived from preclinical studies, and validation in human studies remains limited. It should be emphasized that, although NLRP3 inhibitors have reached clinical stages in other indications (such as neurodegenerative diseases, metabolic diseases, and cardiovascular diseases), these results primarily validate the druggability of the NLRP3 target itself and cannot be directly equated with clinical efficacy in knee OA. Dedicated clinical trials specifically designed for knee OA populations with appropriate clinical endpoints are required to establish therapeutic benefit.