M2 Macrophage‐Mimetic and ROS‐Sensitive Hybrid Nanoplatform for Targeted Alleviation of Rheumatoid Arthritis

Rheumatoid arthritis (RA) constitutes the most prevalent inflammatory arthropathy globally, which is typically marked by synovitis and deteriorating joint damage. Regrettably, RA remains incurable owing to insufficient therapeutic response along with severe side reactions of available treatments. To overcome these formidable obstacles, an M2 macrophage membrane-cloaked, ROS-sensitive lipid-gated, and herbal anti-arthritic agent celastrol (Cel)-loaded hybrid silica nanosystem (Cel@M2-L-MSN) was established to reshape the intricate RA microenvironment. Benefiting from cell membrane camouflaging, Cel@M2-L-MSN inherited the inflammation-homing capability of M2 macrophages and selectively accumulated in the inflamed joints, where excessive ROS triggered Cel release from the mesopores to exert anti-inflammatory and antioxidative effects for joint protection. Moreover, Cel@M2-L-MSN demonstrated strengthened anti-inflammatory capability by robustly sponging multiple pro-arthritogenic factors including TNF-α, IL-1β, and CCL-2. In adjuvant-induced arthritis (AIA) rats, Cel@M2-L-MSN tremendously alleviated arthritis symptoms, mitigated cartilage and bone degeneration, and attenuated major organ injuries by playing multiple roles including inflammation downregulation, ROS clearance, and macrophage repolarization. Furthermore, Cel@M2-L-MSN substantially enhanced the cyto/hemocompatibility of free Cel and manifested good biosafety in vivo. Collectively, this study presents a biohybrid and stimuli-responsive nanomedicine for targeted RA remission, which also holds great promise for the clinical intervention of a wide spectrum of refractory inflammatory diseases.