A Homing Peptide Modified Neutrophil Membrane Biomimetic Nanoparticles in Response to ROS/inflammatory Microenvironment for Precise Targeting Treatment of Ischemic Stroke

Abstract

Oxidative stress induced by ischemia-reperfusion causes severe secondary injury in stroke patients. The blood-brain barrier (BBB) and the challenges in targeting the stroke core hinder the therapeutic effect of drugs. This study introduces a precise biomimetic drug delivery system called SHp-NM@Edv/RCD (SNM-NPs), which possesses multiple stepwise targeting capabilities. SNM-NPs are encapsulated by the neutrophil membranes (NMs) and exhibit a targeting effect (5.16-fold) on the inflammatory microenvironment. The modification of stroke-homing peptides (SHp) makes SNM-NPs target damaged neurons faster, with a targeting efficiency 5.68 times higher than that of β-cyclodextrins (RCD). Then, RCD encapsulated in SNM-NPs responds to reactive oxygen species (ROS), leading to the release of edaravone (Edv), scavenges ROS, inhibits neuroinflammation, and reduces neuronal apoptosis by 90%. Mechanistically, SNM-NPs deliver Edv precisely to the cerebral ischemia-reperfusion injury (CIRI) site, resulting in the elimination of ROS, a decrease in the number of microglia, an improvement in tubulin expression in neurons, and the inhibition of neuronal apoptosis through Caspase 3 pathway. Preliminary experiments also show that SNM-NPs exhibit a good safety profile both in intravenous therapy and in vitro cell experiments. As a result, SNM-NPs hold promise for further development as effective and safe agents for target therapy of CIRI and other diseases.