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

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.