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In this study, chondroitin sulphate proteoglycans (CSPGs) are identified as key regulators of scar maturation via a pathogenic microglia\u2013astrocyte axis. CSPGs promote the transition of reactive astrocytes (RAs) into scar\u2010forming astrocytes (SAs) by inducing a pro\u2010inflammatory microglial phenotype. Mechanistically, CSPGs suppress cytochrome P450 (CYP450)\u00a0enzyme activity in microglia, disrupting metabolic homeostasis and perpetuating inflammatory responses. Targeted degradation of CSPGs reprogrammes microglia toward an anti\u2010inflammatory state, thereby attenuating SA differentiation and fibrotic matrix deposition. To enable spatiotemporally precise intervention, a reactive oxygen species\u2010responsive, connective tissue growth factor\u2010binding fusogenic lipopolyplex for RA\u2010targeted 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\u2010free 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.<\/jats:p>","DOI":"10.1002\/advs.202516269","type":"journal-article","created":{"date-parts":[[2025,11,12]],"date-time":"2025-11-12T10:00:37Z","timestamp":1762941637000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Disrupting CSPG\u2010Driven Microglia\u2013Astrocyte Crosstalk Enables Scar\u2010Free Repair in Spinal Cord Injury"],"prefix":"10.1002","volume":"13","author":[{"given":"Yufei","family":"Zheng","sequence":"first","affiliation":[{"name":"Department of Orthopaedic Surgery Sir Run Run Shaw Hospital Zhejiang University School of Medicine  Hangzhou Zhejiang 310016 China"},{"name":"Key Laboratory of Mechanism Research and Precision Repair of Orthopaedic Trauma and Aging Diseases of 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