Magnesium silicate nanosheets enable sustained hydrogen release to attenuate secondary brain injury following intracerebral hemorrhage.

BACKGROUND: Intracerebral hemorrhage (ICH) is a devastating stroke subtype with high mortality and disability, primarily driven by secondary brain injury involving oxidative stress, neuroinflammation, and apoptosis. Molecular hydrogen (H₂) exhibits potent neuroprotective effects; however, its clinical translation is limited by poor bioavailability and the lack of sustained delivery strategies. METHODS: pH-responsive magnesium silicate nanosheets (MGNs) were synthesized and characterized for morphology, composition, and hydrogen-release behavior. A collagenase-induced ICH mouse model was used to evaluate the therapeutic efficacy of orally administered MGNs. Neurological outcomes, brain edema, histopathology, apoptosis, and inflammatory responses were assessed using behavioral tests, staining, Western blotting, and ELISA. Therapeutic performance was compared with conventional 3% hydrogen inhalation, and biosafety was systematically evaluated. RESULTS: MGNs exhibited a two-dimensional structure and enabled sustained hydrogen release, particularly under acidic conditions. MGNs treatment significantly improved neurological function, reduced brain edema and hematoma volume, preserved neuronal integrity, and attenuated secondary brain injury in a dose-dependent manner. Mechanistically, MGNs suppressed neuronal apoptosis and reduced pro-inflammatory cytokine levels. MGNs demonstrated superior neuroprotection compared with hydrogen inhalation and showed favorable biosafety profiles. CONCLUSIONS: MGNs represent a safe and effective hydrogen-releasing nanoplatform that alleviates secondary brain injury after ICH, highlighting their potential for translational neuroprotective therapy.