Immuno‐Neuroprotectants Facilitate Neurological Recovery via Sequestration of Neutrophil Extracellular Traps (NETs) and Promotion of Neuroregeneration

ABSTRACT Maintaining nerve integrity and rescuing/regenerating injured neurons are pivotal for spinal cord injury (SCI) repair. Herein, an immuno‐neuroprotectant (INPT) is developed to mitigate secondary SCI and promote neuroregeneration via sequestration of neutrophil extracellular traps (NETs) and targeted delivery of brain‐derived neurotrophic factor (BDNF). To construct the INPT, positively charged BDNF is engineered into negatively charged A‐BDNF nanoparticles (A‐BDNF NPs) via reversible modification with adenosine triphosphate, and A‐BDNF NPs are further coated with polySia‐overexpressing microglia membrane (PBM). In SCI mice, intravenously injected INPT effectively accumulates in the injured spinal cord and then binds to NETs through the over‐expressed polySia on PBM. This binding triggers PBM shedding from the NPs, and thereby, phosphatidylserine localized at the cytoplasmic leaflet of PBM is exposed and displayed on the NETs surface. Consequently, the PBM‐bound NETs are cleared by phagocytes via efferocytosis, which provokes neuroprotective immune responses. Meanwhile, the mildly acidic environment triggers traceless restoration of A‐BDNF NPs to the native BDNF to foster neuroregeneration. Thus, PBM‐mediated NETs sequestration cooperates with BDNF‐mediated neuroregeneration to restore neurological recovery. This study provides an enlightened approach for remedying NET‐associated pathophysiological aberrations and also renders a facile yet effective platform for biomacromolecule delivery to the central nervous system.