CD80-targeted songorine nanotherapy restores PINK1-dependent mitophagy in proinflammatory macrophages for osteoarthritis treatment

Synovial macrophage-mediated inflammation and mitochondrial dysfunction are increasingly implicated in osteoarthritis (OA) progression, yet targeted restoration of mitochondrial quality control remains challenging. Here, we developed a macrophage-targeted, targeted delivery nanoplatform (CBP-NPs@Song) by conjugating a CD80-binding peptide to songorine-loaded lipid nanoparticles for preferential and CD80-dependent delivery to proinflammatory (M1) macrophages. CBP-NPs@Song significantly enhanced intracellular drug accumulation and improved multiple indices of mitochondrial function and integrity in inflammatory macrophages. Mechanistically, songorine stabilized PINK1 by reducing its ubiquitination and proteasomal degradation, thereby activating the PINK1–Parkin mitophagy pathway, supporting enhanced clearance of damaged mitochondria through PINK1-associated mitochondrial quality-control processes, and suppressing NLRP3 inflammasome activation. Targeted mitochondrial regulation in macrophages attenuated the adverse effects of proinflammatory macrophages on co-cultured chondrocytes and protected chondrocytes from oxidative and inflammatory injury. In vivo, CBP-NPs@Song exhibited prolonged intra-articular retention with minimal systemic exposure, significantly attenuating synovial inflammation, osteophyte formation, and cartilage degeneration in OA rats. This study presents a targeted nanotherapeutic strategy that integrates selective immunomodulation with mitochondrial quality control, offering a potential strategy for structure-preserving and immunomodulatory OA therapy. Proposed mechanism of CD80-targeted Songorine nanotherapy for osteoarthritis. CBP-NPs@Song preferentially target CD80-expressing proinflammatory macrophages and enhance intracellular Songorine delivery. Songorine treatment is associated with reduced PINK1 ubiquitination and prolonged PINK1 stability, supporting PINK1/Parkin-dependent mitochondrial quality control. This reduces mitochondrial ROS and NLRP3/Caspase-1/IL-1β signaling, thereby attenuating macrophage-to-chondrocyte inflammatory crosstalk and alleviating osteoarthritis-associated joint damage.