Biomimetic Hydrogel System Targeting S100A8 Centered Neuroimmune Crosstalk and Hypoxia Induced Neuronal Injury

ABSTRACT Tissue hypoxia and neuroinflammation are major drivers of secondary injury after traumatic brain injury (TBI). S100A8, a pro‐inflammatory damage‐associated molecular pattern, is involved in pathological neuron–microglia signaling and may amplify secondary damage. However, effective interventions targeting S100A8‐centered neuroimmune crosstalk remain lacking. Here, we developed a multifunctional biomimetic hydrogel system, HPC@Gel, by integrating modified hemoglobin nanoparticles and curcumin‐based carbon quantum dots into a hyaluronic acid–collagen hydrogel to disrupt this vicious cycle. In vitro, hypoxic HT22 neurons, LPS‐stimulated BV2 microglia, and an HT22–BV2 Transwell model were used to evaluate neuroprotection and neuroimmune regulation. HPC@Gel markedly downregulated S100A8 expression and attenuated pathological neuron–microglia 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‐mediated neuroimmune crosstalk.