A hydrogel-based nanoparticles sustained-release system selectively targeting pro-inflammatory microglia for spinal...

Spinal cord injury (SCI) often results in irreversible neurological deficits, primarily due to chronic neuroinflammation driven by activated proinflammatory microglia. Effective therapeutic interventions require both precise targeting of pathological immune cells and sustained modulation of the inflammatory microenvironment. Here, we present a cell specific, hydrogel-based nanoparticle system (MG1-MM@Candesartan-Gel) designed for the selective and prolonged delivery of the angiotensin II type 1 receptor (AT1R) antagonist Candesartan to proinflammatory microglia. The platform integrates microglia membrane-coated liposomes functionalized with MG1 peptides to achieve high-affinity targeting, while encapsulation within an injectable, photo crosslinked hydrogel enables localized, sustained release. In a mouse model of SCI, MG1-MM@Candesartan-Gel effectively reprogrammed microglial phenotypes, attenuated neuroinflammation and scar formation, promoted axonal regeneration and vascular remodeling, and significantly enhanced functional recovery. Importantly, selective microglial targeting minimizes endothelial uptake of Candesartan, reducing potential vascular side effects. This biomimetic delivery strategy provides a promising approach for precision modulation of neuroinflammation and targeted neural repair following CNS injury.