Reprogramming mitochondrial metabolism to enhance macrophages polarization by ROS-responsive nanoparticles for osteoarthritis.

Osteoarthritis (OA) is a chronic low-grade inflammatory joint disease closely related to the inflammatory pathological microenvironment caused by synovial M1 macrophages. In contrast to the proinflammatory role of M1 macrophages, M2 macrophages contribute to anti-inflammatory responses and tissue repair. Therefore, shifting the M2/M1 phenotype ratio in favor of M2 macrophages has become a promising therapeutic strategy for OA. However, current therapeutics cannot penetrate the synovium and only show limited drug retention time. Herein, we developed an OA microenvironment-responsive nanocarrier with thioketal bonds in the main chain and β-1,3-d-glucan and triphenylphosphine units in the side chain, which can respond to reactive oxygen species (ROS) and target macrophages and mitochondrial aggregation. For OA treatment, 4-octyl itaconate and dexamethasone were encapsulated within the nanocarrier, forming HBPTG@OD that effectively eliminated mitochondrial ROS and inducible nitric oxide synthase in M1 macrophages. HBPTG@OD significantly suppressed the release of inflammatory factors by macrophages and thereby reducing chondrocyte death. In vivo studies in a destabilized medial meniscus (DMM)-induced OA model showed that HBPTG@OD effectively converted M1 synovial macrophages to M2 macrophages, consequently delaying chondrogenic apoptosis. This study presents a nanocarrier-based strategy that effectively repolarizes M1 macrophages, demonstrating great promise for the treatment of OA.