Macrophage Membrane‐Reversibly Cloaked Nanotherapeutics for the Anti‐Inflammatory and Antioxidant Treatment of Rheumatoid Arthritis

Abstract During rheumatoid arthritis (RA) development, over‐produced proinflammatory cytokines represented by tumor necrosis factor‐α (TNF‐α) and reactive oxygen species (ROS) represented by H₂O₂ form a self‐promoted cycle to exacerbate the synovial inflammation and tissue damage. Herein, biomimetic nanocomplexes (NCs) reversibly cloaked with macrophage membrane (RM) are developed for effective RA management via dual scavenging of TNF‐α and ROS. To construct the NCs, membrane‐penetrating, helical polypeptide first condenses TNF‐α siRNA (siTNF‐α) and forms the cationic inner core, which further adsorbs catalase (CAT) via electrostatic interaction followed by surface coating with RM. The membrane‐coated NCs enable prolonged blood circulation and active joint accumulation after systemic administration in Zymosan A‐induced arthritis mice. In the oxidative microenvironment of joints, CAT degrades H₂O₂ to produce O₂ bubbles, which shed off the outer membrane layer to expose the positively charged inner core, thus facilitating effective intracellular delivery into macrophages. siRNA‐mediated TNF‐α silencing and CAT‐mediated H₂O₂ scavenging then cooperate to inhibit inflammation and alleviate oxidative stress, remodeling the osteomicroenvironment and fostering tissue repair. This study provides an enlightened strategy to resolve the blood circulation/cell internalization dilemma of cell membrane‐coated nanosystems, and it renders a promising modality for RA treatment.