Ultrasound-Programmable ROS-Responsive Hydrogel Orchestrates Staged Immunomodulation and Neurorepair after Intracerebral Hemorrhage.

Abstract

Intracerebral hemorrhage (ICH) remains a highly lethal and disabling subtype of stroke, and the lack of effective disease-modifying therapies largely reflects the complexity of its secondary injury mechanisms: oxidative stress predominates early and fuels neuroinflammation, whereas impaired neurorepair persists into the subacute phase. Microglia orchestrate these stage-dependent responses and represent a tractable target for shifting perihematomal pathology from damage amplification toward repair. In this study, we developed an injectable, reactive oxygen species (ROS)-responsive therapeutic platform that combines local ROS scavenging with low-intensity-focused ultrasound (LIFU)-enhanced delivery of immunomodulatory and neurotrophic cues. A self-curing polyvinyl alcohol (PVA)-TSPBA hydrogel, hereafter referred to as PT, was engineered to scavenge ROS and to co-encapsulate IL-4 with porous PLGA microspheres containing NT-3, forming IL4-NT3@PT, which gelled rapidly within the operational observation window, exhibited brain-compatible mechanics, showed CSF-like degradability, and scavenged H2O2. In vitro, IL4-NT3@PT reduced oxidative burden and corrected pro-inflammatory microglial bias, with stronger effects after LIFU triggering. In vivo, LIFU-triggered IL4/NT3@PT accelerated lesion resolution and improved motor recovery, while transcriptomic and histological analyses supported immune-network reprogramming, attenuation of oxidative stress and neuroinflammation, reduced microglial activation, and improved tissue preservation. An ultrasound-actuated, injectable ROS-scavenging hydrogel platform enabling sequential IL-4/NT-3 delivery provides a minimally invasive platform for phase-adapted intervention in hemorrhagic brain injury.