Development of a biomimetic manganese dioxide nanoreactor delivery system: Combination of biomimetic platelet/M2 microglia hybrid membrane with Astragaloside IV for the treatment of ischemic stroke

Abstract

Conventional nanotherapeutics suffer from rapid immune clearance and insufficient accumulation in ischemic lesions. To overcome these bottlenecks, a stimuli-responsive biomimetic immunomodulatory delivery system was engineered by fusing platelet and M2 microglial membranes onto hollow mesoporous manganese dioxide nanoparticles loaded with the neuroprotective drug Astragaloside IV. The results show that this integrated nanoplatform fully leverages the synergistic properties of its biomimetic shell. Tracing the nanoparticles with the fluorescent dye Did revealed that the integrated nanoplatform exhibited more pronounced fluorescent enrichment in ischemic brain tissue; both in vivo and ex vivo imaging supported its specific homing ability. In a mouse model of middle cerebral artery occlusion and reperfusion, the platform significantly reduced the extent of cerebral infarction, alleviated neuronal damage caused by ischemia-reperfusion, and improved neurovascular integrity and neurological function. Furthermore, the platform mitigated oxidative stress in ischemic brain tissue, curtailed the inflammatory response, and facilitated a transition in microglial phenotype toward an anti-inflammatory and reparative state. Bioinformatics results indicate that this platform significantly alters gene expression profiles following cerebral ischemia-reperfusion. Differential expression and functional enrichment analyses further point to biological processes related to inflammation and immune regulation. These findings demonstrate that this biomimetic targeted nanoplatform integrates biomimetic targeting, reactive oxygen species scavenging, and immune modulation capabilities, thereby providing a new therapeutic platform technology for the precise delivery of therapeutic agents and the remodeling of the pathological microenvironment in ischemic stroke.