Yam-Derived Vesicles Alleviate Osteoarthritis via miRNA-Mediated Suppression of the TLR4-TRAF6 Signaling Axis.

Osteoarthritis (OA) is a degenerative joint disease, for which effective disease-modifying therapies remain lacking. Here, we report yam-derived nanovesicles (YDNVs) as a plant-derived exosome-like nanoplatform with intrinsic therapeutic activity for OA treatment. YDNVs exhibited typical nanoscale vesicular characteristics and were efficiently internalized by chondrocytes via clathrin-mediated endocytosis. Through enzymatic pretreatment and multi-omics analyses, RNA-particularly microRNAs (miRNAs)-was identified as the primary bioactive component mediating their anti-inflammatory effects. Mechanistic studies further confirmed that aof-miR168a directly binds to the 3' untranslated regions of TLR4 and TRAF6, thereby suppressing downstream inflammatory signaling. To enhance targeting and therapeutic efficacy, a cartilage-targeting peptide-modified system (YDNVs-CAP) was engineered via membrane insertion of a cholesterol-anchored conjugate. This modification significantly improved cellular uptake, cartilage targeting, and intra-articular retention. Functionally, YDNVs-CAP effectively alleviated inflammation, oxidative stress, and extracellular matrix degradation in vitro, and markedly attenuated OA progression in a destabilization of the medial meniscus (DMM) mouse model. Collectively, this study establishes an RNA-mediated therapeutic mechanism for plant-derived nanovesicles and highlights YDNVs-CAP as a promising biomimetic nanoplatform for disease-modifying OA therapy.