Multi‐Target Nanoscavengers for Interrupting the Feed‐Forward Inflammatory Cycle in Autoimmune Diseases

Abstract In autoimmune diseases (AIDs), the interplay of various inflammatory mediators, including cell‐free DNA (cfDNA), reactive oxygen species (ROS), and pro‐inflammatory cytokines, contributes to a self‐amplified inflammatory cascade that greatly limits the efficacy of existing single‐target therapies. Herein, biomimetic nanoparticles (NPs) with reversible macrophage membrane (RM) cloaking are developed to scavenge multiple inflammatory mediators for the multifaceted immunomodulation against AIDs. The NPs are constructed by adsorbing catalase (CAT) onto the cationic, spherical polypeptide (GP), followed by surface coating with RM. Because of the RM coating, the NPs feature long blood circulation and efficient inflammation homing after systemic administration. In the inflamed tissues, RM neutralizes multiple pro‐inflammatory cytokines and CAT decomposes H 2 O 2 to alleviate the oxidative stress. Meanwhile, the O 2 bubbles generated from H 2 O 2 decomposition propels shedding of RM, thus exposing inner GP to mediate robust cfDNA scavenging. Consequently, the NPs effectively alleviate inflammation and facilitate tissue repair in mouse models of AIDs including rheumatoid arthritis and inflammatory bowel disease. This study reports a bio‐inspired strategy for the multi‐target interruption of the self‐amplified inflammatory cascade, and renders promising implications for the clinical management of AIDs.