Spatiotemporally Controllable In Situ Hydrogels Enabled by Nanobottle‐Mediated Encapsulation Technology for Stage‐Specific Synergistic Therapy of Osteoarthritis

ABSTRACT Osteoarthritis (OA) is a chronic joint disorder characterized by synovial inflammation and progressive cartilage degeneration. Current pharmacological and surgical interventions can relieve symptoms but fail to achieve a definitive cure. Herein, we developed a novel spatiotemporally controllable in situ hydrogel using nanobottle‐mediated encapsulation technology for stage‐specific synergistic therapy of OA. Polydopamine (PDA) nanobottles were engineered to co‐encapsulate CuCl 2 and kartogenin (KGN) using natural fatty acids as phase‐change materials, and subsequently mixed with thiourea‐modified hyaluronic acid (HA‐NCSN) containing diclofenac sodium (DS). Notably, upon near‐infrared (NIR) irradiation, Cu 2+ released from PDA nanobottles dynamically chelated with HA‐NCSN, triggering in situ gelation while simultaneously enabling spatiotemporally programmable drug release, featuring rapid DS release and sustained KGN release. More importantly, in vitro studies revealed that the HDPCK hydrogels effectively alleviated inflammatory microenvironments, protected chondrocytes from apoptosis, and promoted BMSCs differentiate to chondrocytes. Consistently, in vivo evaluations demonstrated significant inhibition of cartilage degeneration in an ACLT‐induced OA model and robust cartilage regeneration in a full‐thickness cartilage defect model. Overall, this work developed a novel and universal strategy for constructing spatiotemporally controllable in situ hydrogels, and it holds great potential for the treatment of OA as well as other degenerative diseases.