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Single\u2010target and traditional multi\u2010target therapies, derived from individual drugs, show limited efficacy in addressing these interconnected events, due to spatiotemporal heterogeneity of action in single\u2010target components. This highlights the urgent need for not only new therapeutic targets, but advanced multi\u2010target drugs. Herein, we identify elevated cell\u2010free DNA (cfDNA), a key neuroinflammatory driver, as correlated with SAH severity and poor prognosis, suggesting its therapeutic potential. Furthermore, a novel \u201cin situ proliferation\u201d strategy is proposed and a flexible multi\u2010target peptide nanoparticle is developed through co\u2010assembling matrix metalloproteinase\u20102 responsive cationic peptide and glutathione peroxidase\u2010mimicking peptide (GPXP). Upon reaching injury lesions, this system splits into two individual drugs: cationic peptide scavenges pathological cfDNA and inhibits microglia\u2010mediated neuroinflammation, while GPXP protects neurons against oxidative damage and neuronal apoptosis\/ferroptosis. Consequently, this strategy proves superior therapeutic effects on reducing secondary brain injury and promoting neurofunctional recovery in SAH mice. These findings not only highlight the essential role of cfDNA in SAH but offer a flexible resolution to advance multi\u2010target combinational therapy.<\/jats:p>","DOI":"10.1002\/advs.202417456","type":"journal-article","created":{"date-parts":[[2025,5,30]],"date-time":"2025-05-30T05:31:37Z","timestamp":1748583097000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["In Situ Proliferating Peptide Nanoparticle Augments Multi\u2010Target Intervention of Secondary Brain Damage Following Subarachnoid Hemorrhage"],"prefix":"10.1002","volume":"12","author":[{"given":"Yibin","family":"Zhang","sequence":"first","affiliation":[{"name":"Department of Neurosurgery Neurosurgery Research Institute The First Affiliated Hospital Fujian Medical University  Fuzhou Fujian 350005 China"},{"name":"Department of Neurosurgery National Regional Medical Center Binhai Campus of the First Affiliated Hospital Fujian Medical University  Fuzhou 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