ROS-triggered smart nanoplatform promotes osteoarthritis repair by modulating macrophage polarization and mitochondrial homeostasis

Oxidative stress and inflammation intertwine to form a self-amplifying “vicious cycle”, posing the core factor driving the progression of osteoarthritis (OA). Disrupting this cycle by regulating macrophage polarization, reducing oxidative stress, and maintaining mitochondrial homeostasis is a key strategy to fundamentally halt OA progression. In this study, a ROS-triggered intelligent nanodelivery system (CS@mPDA@Res) was developed to effectively promote OA repair. The system employs mesoporous polydopamine (mPDA) loaded with resveratrol (Res) as the core. By leveraging the high specific surface area and acid resistance of mPDA, this system enables sustained drug release within the OA joint microenvironment. Subsequently, the mPDA@Res nanoparticles were further coated with thioketal (TK)-modified chitosan (CS) as an outer shell. The CS shell disassembles upon ROS stimulation, enabling on-demand release of Res to efficiently promote OA repair through its anti-inflammatory and antioxidant activities. The results demonstrated that CS@mPDA@Res exhibits ROS-triggered intelligent drug release properties and excellent free radical scavenging capacity. In vitro cellular experiments showed that CS@mPDA@Res effectively modulates macrophage polarization, and alleviate oxidative stress-induced mitochondrial dysfunction and cartilage matrix degradation in chondrocytes. In vivo studies further revealed that CS@mPDA@Res treatment significantly alleviates OA joint damage. On day 28 of treatment, OA rats in the CS@mPDA@Res group exhibited 74.1% and 68.69% reductions in Mankin score and International Cartilage Repair Society (ICRS) score, respectively, compared to the model group. In summary, CS@mPDA@Res offers a novel and highly promising therapeutic approach for OA treatment.