Advancing Recovery Post‐Spinal Cord Injury: Nanoparticle‐Mediated Reprogramming of Peripheral Macrophages

Abstract Spinal cord injuries (SCIs) often result in secondary damage; therefore, interventions beyond current cell transplantation methods must be explored. The innate phagocytic propensity of macrophages are exploited for artificially aged erythrocytes and developed a delivery system fusing erythrocytes with reactive oxygen species (ROS)‐reactive nanoparticles prepared from a diselenide‐bond cross‐linked organic compound. The system targets peripheral blood macrophages, delivering anti‐glutamate drug‐loaded nanoparticles to the SCI site, releasing the drug upon ROS stimulation. This efficiently enables targeted drug delivery and reprograms peripheral macrophages through synergistic action with erythrocytes and encapsulated nucleic acids, effectively modulating the immune microenvironment in the SCI zone (significantly reduces neuronal apoptosis and alters the macrophage phenotype in the SCI region). The approach effectively addresses glutamate toxicity and immune inflammation by effectively regulating the lesion microenvironment, providing protection to neurons and creating favorable conditions for regeneration. Departing from the conventional “red blood cell backpack” model, the “chocolate chip cookie” concept is paradigm‐altering, enabling multifaceted erythrocyte functions. Collectively, the system comprehensively enhances the post‐SCI microenvironment. Its efficacy in SCI treatment and innovative drug delivery approach open new possibilities for neural function recovery. By laying the groundwork for future clinical applications, the research pioneers a transformative path toward advancing SCI therapeutics.