Abstract
Cytoprotection has emerged as an effective therapeutic strategy for mitigating brain injury following acute ischemic stroke (AIS). The sulfonylurea receptor 1-transient receptor potential M4 (SUR1-TRPM4) channel plays a pivotal role in brain edema and neuroinflammation. However, the practical use of the inhibitor glyburide (GLB) is hindered by its low bioavailability. Additionally, the elevated reactive oxygen species (ROS) after AIS exacerbate SUR1-TRPM4 activation, contributing to irreversible brain damage. To overcome these challenges, GLB and superoxide dismutase (SOD) were embedded in a covalent organic framework (COF) with a porous structure and great stability. The resulting S/G@COF demonstrated significant improvements in survival and neurological functions. This was achieved by eliminating ROS, preventing neuronal loss and apoptosis, suppressing neuroinflammation, modulating microglia activation, and ameliorating blood-brain barrier (BBB) disruption. Mechanistic investigations revealed that S/G@COF concurrently activated the Wnt/β-catenin signaling pathway while suppressing the upregulation of SUR1-TRPM4. This study underscores the potential of employing multi-target therapy and drug modification in cytoprotective strategies for ischemic stroke.