ReprogrammingMacrophage Phenotype Using a ReactiveOxygen Species-Responsive Liposome Delivery System for InflammationMicroenvironment Remodeling and Osteoarthritis Treatment

The progression of osteoarthritis (OA) is closely linked to synovial inflammation caused by an imbalance between M1 and M2 macrophages. To tackle this problem, we developed a liposome responsive to reactive oxygen species (ROS), modified with folic acid ligands to target M1-polarized macrophages, and loaded with the anti-inflammatory agent dimethyl fumarate (DMF). This liposome-based drug delivery system was designed to reprogram macrophage phenotype to remodel the inflammatory microenvironment in the joint cavity and alleviate OA degeneration. The liposome we prepared had a suitable size and negative zeta potential, with uniform size, good stability in aqueous solution, and excellent biocompatibility. Laboratory tests showed that these DMF-filled liposomes notably decreased high levels of ROS in M1-type macrophages and shifted macrophage polarization via the Nrf2/HO-1 pathway, which in turn lessened inflammation in chondrocytes and averted their apoptosis. Additionally, animal studies demonstrated that liposomes containing DMF exhibited notable anti-inflammatory properties, significantly reduced synovial inflammation, safeguarded injured cartilage, reversed changes in subchondral bone, and effectively slowed the progression of osteoarthritis in a mouse model induced by anterior cruciate ligament transection (ACLT). Therefore, ROS-responsive liposomes targeting M1-polarized macrophages represent a promising and valuable approach for OA treatment.