In Situ Proefferocytosis Microspheres as Macrophage Polarity Converters Accelerate Osteoarthritis Treatment

Abstract Efferocytosis in macrophages typically engages an anti‐inflammatory positive feedback regulatory mechanism. In osteoarthritis (OA), characterized by imbalanced inflammatory homeostasis, the proinflammatory state of macrophages in the immune microenvironment can be reversed through enhanced efferocytosis. This study develops an in situ proefferocytosis hydrogel microsphere (macrophage polarity converter, H‐C@IL) for OA treatment. Immunoliposomes (IL), CD16/32 antibody‐modified clodronate liposomes, are initially prepared using the Re‐emulsion method. Then, the IL is loaded into CCL19‐modified HAMA microspheres through microfluidic technology. In vitro, H‐C@IL can specifically recruit M0 and M1 macrophages via CCL19, induce apoptosis in M1 macrophages through secondary targeting with IL, and provide “Find/Eat‐me” signals to enhance in situ efferocytosis. Additionally, it promotes macrophage polarization toward the M2 phenotype. In vivo, behavioral, imaging, and histological analyses demonstrate that H‐C@IL effectively facilitates macrophage polarization toward M2, inhibits inflammation, and promotes cartilage regeneration. Mechanistically, H‐C@IL enhances efferocytosis by activating proteins such as PROS1 and TIMD4 in M0 macrophages. Concurrently, signaling pathways, including PQLC2‐Arg‐Rac1 and Pbx1/IL‐10, are activated to drive the polarization of macrophages from M0 to M2. In summary, H‐C@IL promotes M0 macrophage efferocytosis in situ, facilitates macrophage polarization toward M2, restores inflammatory homeostasis, and promotes cartilage regeneration, offering a comprehensive treatment strategy for OA.