Immuno‐Engineered Nanodecoys for the Multi‐Target Anti‐Inflammatory Treatment of Autoimmune Diseases

Abstract Overactivated T cells and overproduced pro‐inflammatory cytokines form a self‐amplified signaling loop to continuously exacerbate the dysregulated inflammatory response and propel the progression of autoimmune diseases (AIDs). Herein, immuno‐engineered nanodecoys (NDs) based on poly(lactic‐co‐glycolic acid) nanoparticles coated with programmed death‐ligand 1 (PD‐L1)‐expressing macrophage membrane (PRM) are developed to mediate multi‐target interruption of the self‐promoted inflammatory cascade in AIDs. The PRM collected from IFN‐γ‐treated RAW 264.7 cells possesses elevated surface levels of adhesion molecule receptors and pro‐inflammatory cytokine receptors, and, thus, systemically administered PRM NDs afford higher accumulation level in inflamed tissues and stronger scavenging efficiency toward multiple pro‐inflammatory cytokines. More importantly, IFN‐γ treatment induces remarkable PD‐L1 expression on PRM, thereby allowing PRM NDs to bind membrane‐bound programmed death‐1 (PD‐1) on CD4⁺ T cell surfaces or neutralize free soluble PD‐1, which reconstructs the PD‐1/PD‐L1 inhibitory axis to suppress CD4⁺ T cell activation and restore immune tolerance. As such, PRM NDs provoke potent and cooperative anti‐inflammatory and immune‐suppressive efficacies to alleviate autoimmune damages in Zymosan A‐induced arthritis mice and dextran sulfate sodium‐induced ulcerative colitis mice. This study provides an enlightened example for the immuno‐engineering of cell‐membrane‐based NDs, rendering promising implications into the treatment of AIDs via multi‐target immune‐modulation.