Reprogramming macrophage polarization via CD44-targeted and ROS-responsive apabetalone-loaded micelles for rheumatoid arthritis treatment.

Current treatments for rheumatoid arthritis (RA) are highly limited by poor joint targeting, systemic toxicity, and an inability to precisely modulate the complex inflammatory microenvironment driven by overactive macrophages and elevated reactive oxygen species (ROS). To address these core challenges, this study developed a novel dual-functional nanoplatform: chondroitin sulfate-thioketal-poly(lactic-co-glycolic acid) (CS-TK-PLGA) micelles designed to encapsulate the anti-inflammatory drug apabetalone (CS/TK/Apa). This system leverages its CS corona for CD44 receptor-mediated uptake by activated macrophages. Subsequently, the ROS-responsive thioketal (TK) linker ensures on-demand drug release triggered by the high oxidative stress unique to the arthritic synovium. Both in vitro and in vivo evaluations demonstrate that CS/TK/Apa micelles effectively promote M1-to-M2 macrophage polarization, suppressing pro-inflammatory pathways. Crucially, the micellar formulation achieved a 2.2-fold increase in systemic exposure compared to the free drug, translating to significantly improved therapeutic efficacy in alleviating joint inflammation, reducing cartilage degradation, and minimizing bone erosion in RA mouse models. Supported by excellent biocompatibility and low systemic toxicity profiles, this CD44-targeted and ROS-responsive CS/TK/Apa nanoplatform offers a compelling precision strategy for RA therapy.