Disrupting CSPG‐Driven Microglia–Astrocyte Crosstalk Enables Scar‐Free Repair in Spinal Cord Injury

Abstract Glial scar formation represents a significant obstacle to neural regeneration following spinal cord injury (SCI), evolving from a protective glial response in the acute phase to a fibrotic and inhibitory barrier in the chronic stage. In this study, chondroitin sulphate proteoglycans (CSPGs) are identified as key regulators of scar maturation via a pathogenic microglia–astrocyte axis. CSPGs promote the transition of reactive astrocytes (RAs) into scar‐forming astrocytes (SAs) by inducing a pro‐inflammatory microglial phenotype. Mechanistically, CSPGs suppress cytochrome P450 (CYP450) enzyme activity in microglia, disrupting metabolic homeostasis and perpetuating inflammatory responses. Targeted degradation of CSPGs reprogrammes microglia toward an anti‐inflammatory state, thereby attenuating SA differentiation and fibrotic matrix deposition. To enable spatiotemporally precise intervention, a reactive oxygen species‐responsive, connective tissue growth factor‐binding fusogenic lipopolyplex for RA‐targeted delivery of the chondroitinase ABC (ChABC) gene is designed. This platform selectively degrades CSPGs at the lesion border, interrupts the maladaptive glial feedback loop, and facilitates scar‐free repair after SCI. These findings reveal a metabolic mechanism underlying glial scarring and propose a precision nanotherapeutic strategy to modulate the SCI microenvironment, thereby enhancing neuronal regeneration and functional recovery.