A Carrier-Free Triple-Drug Co-Assembled Nanoformulation for Synergistic Treatment of Cerebral Ischemia-Reperfusion Injury

Cerebral ischemia-reperfusion injury (CIRI), a critical complication arising from the recanalization of blood flow to the ischemic region of the brain following an ischemic stroke, poses significant challenges in clinical management due to the lack of efficacious therapeutic interventions. This condition markedly impacts the patient prognosis and quality of life. Herein, we developed a carrier-free triple-drug co-assembled nanoformulation, designated as SRPNNPs, to achieve safe and efficient treatment of CIRI. SRPNNPs were prepared by co-assembly of two natural plant-derived small molecule drugs, including ginsenoside Rb1 (Rb1) and 3-n-butylphthalide (NBP), along with probucol (PB). To enhance the capability to cross the blood-brain barrier (BBB), SRPNNPs were further modified with polysorbate 80 (PS 80). Intravenously administered SRPNNPs can adsorb apolipoproteins in circulation, thereby facilitating specific binding to lipoprotein receptors on the cerebral vascular endothelial cells, which promotes their transport across the BBB. Furthermore, SRPNNPs are enriched to the CIRI region and are subsequently internalized by neurons and microglia, where they exert synergistic antioxidant, anti-inflammatory, and neuroprotective effects, thereby achieving effective treatment of CIRI. Overall, our work presents a simple and promising strategy for the targeted treatment of CIRI.