Traumatic brain injury (TBI) remains the major cause of disability and mortality worldwide due to the persistent neuroinflammation and neuronal death induced by TBI. Among them, pyroptosis, a specific type of programmed cell death (PCD) triggered by inflammatory signals, plays a significant part in the pathological process after TBI. Inhibition of neuroinflammation and pyroptosis is considered a possible strategy for the treatment of TBI. In our previous study, exogenous hydrogen sulfide(H₂S) exerted a neuroprotective effect after TBI. Here, we developed a surface-fill H₂S-releasing silk fibroin (SF) hydrogel (H₂S@SF hydrogel) to achieve small-dose local administration and avoid volatile and toxic side effects. We used a controlled cortical impact (CCI) to establish a mild TBI model in mice to examine the effect of H₂S@SF hydrogel on TBI-induced pyroptosis. We found that H₂S@SF hydrogel inhibited the expression of H₂S synthase in neurons after TBI and significantly inhibited TBI-induced neuronal pyroptosis. In addition, immunofluorescence staining results showed that the necroptosis protein receptor-interacting serine/threonine-protein kinase 1 (RIPK1) partially colocalized with the pyroptosis protein Gasdermin D (GSDMD) in the same cells. H₂S@SF hydrogel can also inhibit the expression of the necroptosis protein. Moreover, H₂S@SF hydrogel also alleviates brain edema and the degree of neurodegeneration in the acute phase of TBI. The neuroprotective effect of H₂S@SF hydrogel was further confirmed by wire-grip test, open field test, Morris water maze, beam balance test, radial arm maze, tail suspension, and forced swimming test. Lastly, we also measured spared tissue volume, reactive astrocytes and activated microglia to demonstrate H₂S@SF hydrogel impacts on long-term prognosis in TBI. Our study provides a new theoretical basis for the treatment of H₂S after TBI and the clinical application of H₂S@SF hydrogel. STATEMENT OF SIGNIFICANCE: Silk fibroin (SF) hydrogel controls the release of hydrogen sulfide (H₂S) to inhibit neuronal pyroptosis and neuroinflammation in injured brain tissue. In this study, we synthesized a surface-fill H₂S-releasing silk fibroin hydrogel, which could slowly release H₂S to reshape the homeostasis of endogenous H₂S in injured neurons and inhibit neuronal pyroptosis in a mouse model of traumatic brain injury. Meanwhile, H₂S@SF hydrogel could alleviate brain edema and the degree of neurodegeneration, improve motor dysfunction, anxious behavior and memory impairment caused by TBI, reduce tissue loss and ameliorate neuroinflammation. Our study provides a new theoretical basis for the treatment of H₂S after TBI and the clinical application of H₂S@SF hydrogel.

#	Concept	H-Index	Publications	Citations
1	Medicine	7	7	383
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3	Biochemistry	2	2	48
4	Engineering	1	1	20
5	Natural Sciences	1	1	26

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