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S100A8, a pro\u2010inflammatory damage\u2010associated molecular pattern, is involved in pathological neuron\u2013microglia signaling and may amplify secondary damage. However, effective interventions targeting S100A8\u2010centered neuroimmune crosstalk remain lacking. Here, we developed a multifunctional biomimetic hydrogel system, HPC@Gel, by integrating modified hemoglobin nanoparticles and curcumin\u2010based carbon quantum dots into a hyaluronic acid\u2013collagen hydrogel to disrupt this vicious cycle. In vitro, hypoxic HT22 neurons, LPS\u2010stimulated BV2 microglia, and an HT22\u2013BV2 Transwell model were used to evaluate neuroprotection and neuroimmune regulation. HPC@Gel markedly downregulated S100A8 expression and attenuated pathological neuron\u2013microglia crosstalk. Recombinant S100A8 rescue experiments further showed that exogenous S100A8 partially reversed the protective effects of HPC@Gel, supporting the functional role of S100A8 suppression. In a rat cortical cavity TBI model, HPC@Gel reduced S100A8 expression in neurons and microglia, alleviated neuronal hypoxia, and reversed neuroinflammation. These effects improved the pathological microenvironment, promoted endogenous neural regeneration, and facilitated neurological and cognitive recovery. This study provides a promising therapeutic strategy for TBI by simultaneously targeting hypoxia and S100A8\u2010mediated neuroimmune crosstalk.<\/jats:p>","DOI":"10.1002\/advs.76220","type":"journal-article","created":{"date-parts":[[2026,6,22]],"date-time":"2026-06-22T10:37:27Z","timestamp":1782124647000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Biomimetic Hydrogel System Targeting S100A8 Centered Neuroimmune Crosstalk and Hypoxia Induced Neuronal Injury"],"prefix":"10.1002","volume":"13","author":[{"given":"Peng","family":"Liu","sequence":"first","affiliation":[{"name":"Department of Neurosurgery West China Medical School West China Hospital Sichuan University  Chengdu Sichuan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoyang","family":"Wu","sequence":"additional","affiliation":[{"name":"National Engineering Research Center for Biomaterials College of Biomedical Engineering 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