Bioadhesive Hydrogel With Polyphenol‐Armored Nanogene Rejuvenates Chondrocyte Senescence for Aged Osteoarthritis Therapy

ABSTRACT Chondrocyte senescence, exacerbated by ageing and cellular stress, is a key driver of metabolic imbalance during aged osteoarthritis (OA) progression. Achieving sustained inhibition of chondrocyte senescence while mitigating multifactorial cellular stressors remains challenging in aged OA treatment. In this study, an injectable bioadhesive and lubricating hydrogel, encapsulating miR‐140‐5p (miR‐140)‐loaded and polyphenol‐armored nanoparticles, was developed for rejuvenating senescent chondrocytes in aged OA. Originating from catechol groups, the hydrogel anchors firmly to cartilage tissues, facilitating a sustained reduction in joint friction. It also acts as a local depot for nanoparticles, prolonging their retention within the harsh joint cavity. The polyphenol armor on the nanoparticles preserves miR‐140 activity in the RNase‐ and ROS‐rich senescence microenvironment, prevents premature leakage, and enhances transfection efficiency by overcoming extracellular matrix, cell membrane, and lysosomal barriers. This contributes to the downregulation of senescence‐associated signaling pathways in chondrocytes. Furthermore, the polyphenol armor exhibits catalase‐ and superoxide‐dismutase‐like activity, mitigating mitochondrial dysfunction through targeted ROS scavenging. By integrating these advanced attributes, the hydrogel attenuated chondrocyte senescence and OA progression in an aged rat model, showing great prospects in clinical application.