Injectable Hydrogel Containing RNA-Loaded Liposomes Alleviates Chondrocyte Inflammation by Disrupting BAK1-Mediated mtDNA Maintenance

Osteoarthritis (OA) causes disability and morbidity. The main therapy for OA is chronic treatment, focusing on articular cartilage protection and inflammation control. Mitochondrial DNA (mtDNA) damage plays an important role in cGAS-STING-induced inflammation. Therefore, a strategy involving effective encapsulation of a therapeutic payload is required to avoid mtDNA-related inflammation. Herein, we developed an in situ injectable chitosan hydrogel (ICH) loaded with lipid-BAK1 siRNA nanoparticle complexes that attenuate an increase of mtDNA. ATDC5 cells or bone marrow monocytes under inflammation stimulation were cocultured with siBAK@Lips@ICH. This hydrogel delivers lipid-BAK1 siRNA-loaded liposomes which downregulate BAK1 secretion and decrease mtDNA release, and this contributes significantly to upregulation of cGAS-STING-mediated inflammation. A knee osteolysis model was then established and treated with siBAK@Lips@ICH. Consequently, our data show that the delivery system provides comprehensive protection of cartilage and subchondral bone by ameliorating the whole process of inflammation reversal and amplification.