Nanozyme-Switched Efferocytosis Initiation Platform Orchestrates Pathological Network Reprogramming to Promote Functional Recovery after Spinal Cord Injury.

Abstract

Nerve regeneration after spinal cord injury (SCI) is severely hindered by a hostile microenvironment, where excessive reactive oxygen species (ROS) and uncontrolled inflammation form a vicious cycle, triggering secondary injury cascades. However, most current treatments are single-target strategies, obtaining marginal benefits for the intricate pathological mechanisms after SCI. Herein, we developed a nanozyme-switched efferocytosis initiation platform, termed CM-ApoV, by integrating mesenchymal stem cell-derived apoptotic vesicles (ApoVs) with cerium-melatonin nanozymes (Ce-MT). As a distinct subtype of extracellular vesicles, ApoVs are enriched with functional proteins that mediate immunomodulation. Besides, phosphatidylserine (PtdSer) exposed on the surface of ApoVs serves as a critical "eat me" signal that enables targeted recognition and efferocytosis by microglia, thereby promoting microglial repolarization and modulating their functions. Ce-MT nanozymes were anchored onto ApoVs to enhance their ROS scavenging capacity. In the meanwhile, the reversible attachment and detachment of Ce-MT mask PtdSer during systemic circulation and enable re-exposure of PtdSer in an oxidative microenvironment at the injured site. Consequently, the CM-ApoV system comprehensively remodels the pathological network and establishes a favorable microenvironment for neuronal repair. In a rodent model of SCI, CM-ApoV promoted neuronal survival, modulated microglial function, and reduced glial scar formation, ultimately leading to a significant improvement in motor function. Overall, this system highlights the synergistic therapeutic potential of the nanozyme-ApoV hybrid platform and provides a feasible strategy for multidimensional treatment of SCI.