Yam‐Derived Vesicles Alleviate Osteoarthritis via miRNA‐Mediated Suppression of the TLR4–TRAF6 Signaling Axis

ABSTRACT 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.