• Combined AAV-p65shRNA and AAV-BMP4 gene therapy synergistically enhances chondrocyte regeneration and treats osteoarthritis.
• A 1:1 ratio of AAV-p65shRNA to AAV-BMP4 yields maximal extracellular matrix synthesis and cartilage repair in vitro and in vivo.
• Both inhibition of inflammation (via p65shRNA) and promotion of regeneration (via BMP4) are equally critical for effective osteoarthritis treatment.
• This dual-gene approach offers a novel strategy for early osteoarthritis by simultaneously targeting inflammation and promoting cartilage repair.