Jing He

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.

Parkinson’s disease (PD), the second most common neurodegenerative disorder globally, relies primarily on dopamine replacement therapy for conventional treatment. This approach fails to reverse core pathological processes and is associated with long-term side effects. Recent research on the microbiota-gut-brain axis (MGBA) has revealed that PD pathology may originate in the gut, forming a vicious cycle from the gut to brain through α-synuclein propagation, gut dysbiosis, intestinal barrier disruption, and neuroinflammation. This offers a novel perspective for managing PD through dietary interventions that modulate the gut microbiome. However, single probiotic or prebiotic interventions show limited efficacy. This review systematically introduces the novel concept of “synbiotics combining medicinal plant polysaccharides with probiotics,” aiming to integrate traditional “medicinal food” wisdom with modern microbiome science. The article systematically elucidates the pathological mechanisms of MGBA dysfunction in PD and the intervention mechanisms of probiotics and emphasizes the structural and functional advantages of medicinal plant polysaccharide as superior prebiotics. The core section delves into the multifaceted synergistic mechanisms between these two components: enhancing probiotic colonization and vitality, optimizing microbial metabolic output, synergistically reinforcing the intestinal and blood-brain barriers, and jointly regulating immune and neuroinflammation. This approach targets the MGBA to achieve multi-level intervention for PD.

Background: Photoaging, induced by chronic ultraviolet (UV) exposure, is a multifactorial skin disorder characterized by oxidative stress, inflammation, and extracellular matrix degradation. Ganoderma lucidum glycoprotein (Gl-Gp) exhibits potent antioxidant activity, but its topical application is limited by poor transdermal permeability. This study aimed to develop a microemulsion-based system to enhance Gl-Gp delivery and evaluate its anti-photoaging efficacy. Methods: Gl-Gp was extracted and purified from G. lucidum fruiting bodies and structurally characterized for O-glycosidic linkages and O-GlcNAc modifications. Fourier-transform infrared (FT-IR) spectroscopy further confirmed the polysaccharide–protein complex structure of Gl-Gp. A water-in-oil Gl-Gp microemulsion was prepared and assessed in vitro for antioxidant and cytoprotective effects in HaCaT cells, including reactive oxygen species (ROS) reduction, mitochondrial membrane potential stabilization, and apoptosis inhibition. Transdermal penetration was compared with aqueous Gl-Gp. In vivo efficacy was evaluated in a UV-induced rat model by measuring skin morphology, histology, oxidative stress markers, matrix metalloproteinases, and proinflammatory cytokines. Results: The microemulsion enhanced Gl-Gp stability and transdermal delivery. In vitro, it reduced ROS, preserved mitochondrial function, and decreased apoptosis in HaCaT cells. In rats, topical application attenuated erythema and epidermal hyperplasia, promoted dermal restoration, increased SOD and GSH-Px activities, and decreased MDA, hydroxyproline, MMPs, and inflammatory mediators. Conclusions: The Gl-Gp microemulsion exerts antioxidant, anti-inflammatory, and anti-collagen-degrading effects, representing a promising strategy for transdermal delivery and topical prevention of photoaging.