Reactive oxygen species-responsive sulfated polysaccharide-based nanogels for ischemic stroke: A precision therapy through pathological microenvironment modulation.

Thrombolytic therapy for cardiovascular and cerebrovascular diseases is significantly limited by the short half-life, inadequate targeting specificity, and hemorrhagic complications of conventional therapeutic agents. To overcome these challenges, we developed a dual-functional nanogel (PGS-SP@UK) that integrates P-selectin-mediated thrombus targeting with ROS-responsive drug release. Taking advantage of the P-selectin targeting capability of polyguluronate sulfate (PGS), we synthesized the sulfated polysaccharide with selenocystamine and pinacol phenylboronate (PBAP) to construct an amphiphilic copolymer capable of encapsulating urokinase (UK). Notably, this nanogel exhibited H₂O₂-triggered UK release (85.79 %) while maintaining great stability under physiological conditions. In vitro studies confirmed its neuroprotective effects through modulation of the ferroptosis signaling pathway in an OGD/R-induced model. In vivo studies revealed efficient blood-brain barrier penetration and thrombus-specific accumulation, achieving 84.3 % recovery in cerebral infarct area through synergistic thrombolysis and oxidative stress mitigation. Our study presents an innovative drug delivery system with significant potential for clinical ischemic stroke treatment. STATEMENT OF SIGNIFICANCE: Conventional thrombolytic agents suffer from poor targeting specificity and severe bleeding complications, limiting their clinical efficacy in ischemic stroke treatment. We designed a dual-functional nanogel (PGS-SP@UK) that uniquely integrates P-selectin-mediated active targeting with ROS-responsive drug release mechanisms. This innovative design represents a system to combine polyguluronate sulfate-based thrombus recognition with oxidative stress-triggered urokinase liberation. Our nanogel achieves unprecedented selectivity through dual targeting: bioactive targeting via P-selectin binding and microenvironmental responsiveness to pathological ROS levels. In vivo validation demonstrated exceptional therapeutic outcomes with 84.3 % cerebral infarct recovery while eliminating systemic hemorrhagic risks. This breakthrough establishes a new therapeutic paradigm that transcends current limitations through synergistic thrombolysis and neuroprotection, offering transformative potential for precision medicine in thrombotic disorders.