Engineered Nanoerythrocytes Alleviate Central Nervous System Inflammation by Regulating the Polarization of Inflammatory Microglia

Abstract Microglial polarization is one of the most promising therapeutic strategies for multiple central nervous system (CNS) disorders. However, safe, effective, and controllable microglial regulation still faces formidable challenges. Although some anti‐inflammatory factors promote microglia polarization, their short half‐life, high cost, unpredictable in vivo behavior, and complex delivery operations, hamper their clinical application. Here, inspired by the natural microhemorrhage cleaning mechanism, an MG1 peptide and RVG29 peptide engineered nanoerythrocyte (NEMR) that can reprogram microglia are developed from classical M1 toward alternative M2 by inducing heme oxygenase‐1 (HO‐1), stimulating Notch1/Hes1/Stat3 signaling, and further inhibiting NF‐κB p65 translocation. Moreover, anti‐inflammatory carbon monoxide (CO) and bilirubin produced by endogenous metabolism of heme further reinforces the anti‐inflammatory effect. In middle cerebral artery occlusion and experimental autoimmune encephalomyelitis models, a satisfactory prognosis is achieved, with precise regulation of inflammatory microglia in lesion sites, increased expression of anti‐inflammatory factors, reduced blood–brain barrier permeability, as well as promotion of neurogenesis and functional recovery. Furthermore, NEMR can be integrated with clinical therapeutic agents, which facilitates precise drug delivery to enhance therapeutic effects. Hence, the natural nanoerythrocytes, as a feasible, efficient, safe, and practical tool, provides a new strategy for rebalancing of the immune environment in the CNS disorders.