Therapeutic extracellular vesicles enriched with SNHG5 reprogram autophagy and macrophage polarization in...

Umbilical cord-derived extracellular vesicles (Uc-EVs) offer a promising therapeutic approach for osteoarthritis (OA) by delivering critical regulatory macromolecules. In a papain-induced rat model of OA, intra-articular administration of Uc-EVs markedly reduced synovial inflammation, cartilage degradation, and chondrocyte apoptosis while promoting collagen deposition, autophagy, and M2 macrophage polarization. RNA sequencing revealed that the long noncoding RNA SNHG5 is highly enriched in Uc-EVs, which plays a pivotal role in mediating their therapeutic efficacy of. Mechanistically, SNHG5 interacts with the m6A methyltransferase METTL14, facilitating N6-methyladenosine (m6A) modification of PRKAA1 mRNA, which encodes the AMPKα1 subunit. This modification enhances PRKAA1 transcript stability and translation, activating AMPK signaling, a key regulator of cellular energy homeostasis autophagy. RNA pull-down, RNA immunoprecipitation (RIP), and MeRIP-qPCR confirmed the SNHG5-METTL14-PRKAA1 interaction network. Silencing SNHG5 or pharmacological inhibiting of AMPK abolished the therapeutic benefits of Uc-EVs, leading to increased M1 macrophage polarization and inflammatory cytokine production. These findings elucidate a macromolecular mechanism by which Uc-EVs modulate immune and metabolic responses in OA, highlighting SNHG5-enriched EVs as a novel RNA-based strategy to restore joint homeostasis and halt OA progression.