Neutrophil-Biomimetic “Nanobuffer” for Remodeling the Microenvironment in the Infarct Core and Protecting Neurons in the Penumbra via Neutralization of Detrimental Factors to Treat Ischemic Stroke

Abstract

High level of detrimental factors including reactive oxygen species (ROS) and inflammatory cytokines accumulated in the infarct core and their erosion to salvageable penumbra are key pathological cascades of ischemia-reperfusion injury in stroke. Few neuroprotectants can remodel the hostile microenvironment of the infarct core for the failure to interfere with dead or biofunctionally inactive dying cells. Even ischemia-reperfusion injury is temporarily attenuated in the penumbra by medications; insults of detrimental factors from the core still erode the penumbra continuously along with drug metabolism and clearance. Herein, a strategy named “nanobuffer” is proposed to neutralize detrimental factors and buffer destructive erosion to the penumbra. Inspired by neutrophils’ tropism to the infarct core and affinity to inflammatory cytokines, poly(lactic- c o -glycolic acid) (PLGA) nanoparticles are coated with neutrophil membrane to target the infarct core and absorb inflammatory cytokines; α-lipoic acid is decorated on the surface and cannabidiol is loaded for ROS scavenging and neuroprotection, respectively, to construct the basic unit of the nanobuffer. Such a nanobuffer exerts a comprehensive effect on the infarct area via detrimental factor neutralization and cannabidiol-induced neuroprotection. Besides, the nanobuffer can possibly be enhanced by dynamic ROP (ring-opening-polymerization)-induced membrane cross-fusion among closely adjacent units in vivo. Systematic evaluations show significant decrease of detrimental factors in the core and the penumbra, reduced infarct volume, and improved neurological recovery compared to the untreated group of stroke rats.