Ultrasound-gated nanobubbles for sequential pyroptosis blockade and mechanotransductive neurorepair in sepsis-associated encephalopathy.

Sepsis-associated encephalopathy (SAE) is a life-threatening neuroinflammatory complication of sepsis for which effective treatment remains unavailable. A major challenge is that most therapeutics cannot efficiently cross the blood-brain barrier or simultaneously address the coupled pathological processes driving disease progression, namely microglial pyroptosis and impaired neurotrophic support. Here, we report an ultrasound-gated nanobubble platform designed for SAE that enables sequential pyroptosis blockade and mechanotransduction-mediated neurorepair. The platform consists of sphingosine-1-phosphate-functionalized, disulfiram-loaded nanobubbles (S1P@DSF-NBs), which actively accumulate in inflamed cerebral vasculature via the S1P-S1PR1 axis and serve as a localized reservoir for ultrasound-programmed intervention. Under a dual-ultrasound regimen, low-intensity pulsed ultrasound first induces stable nanobubble oscillation, mechanically activating Piezo1-dependent CREB-BDNF signaling in microglia to restore neurotrophic support. Subsequent high-intensity pulsed ultrasound triggers nanobubble destabilization and localized disulfiram release, leading to gasdermin D inhibition, suppression of pyroptosis, and attenuation of inflammatory amplification. In a murine SAE model, ultrasound-programmed S1P@DSF-NBs reduced systemic and hippocampal inflammation, decreased neuronal loss by 40 %, and improved cognitive performance by 2.24-fold, while reprogramming microglia toward a neuroprotective phenotype and disrupting the pyroptotic inflammatory cascade. These findings demonstrate that ultrasound-programmed nanobubble therapy can concurrently interrupt inflammatory injury and restore neuroprotective signaling in SAE. This work establishes an actively targeted, ultrasound-responsive biomaterials strategy for ultrasound-programmed intervention in SAE and offers a versatile framework for the treatment of other neuroinflammatory disorders.