Neutrophil Membrane-Derived Nanovesicles Alleviate Inflammation To Protect Mouse Brain Injury from Ischemic Stroke

Abstract

Ischemic stroke is an acute and severe neurological disease, resulting in the disability and death. Reperfusion to an ischemic brain is a means to reverse brain damage after stroke; however, this causes secondary tissue damage induced by inflammation responses, called ischemia/reperfusion (I/R) injury. Adhesion of neutrophils to endothelial cells underlies the initiation of inflammation in I/R. Inspired by this interaction, we report a drug delivery system comprised of neutrophil membrane-derived nanovesicles loaded with Resolvin D2 (RvD2) that can enhance resolution of inflammation, thus protecting brain damage during ischemic stroke. In the study, the middle cerebral artery occlusion (MCAO) mouse model was developed to mimic ischemic stroke. Using intravital microscopy of live mouse brain, we real time visualized the binding of nanovesicles to inflamed brain vasculature for delivery of therapeutics to ischemic stroke lesions. We also observed that RvD2-loaded nanovesicles dramatically decreased inflammation in ischemic stroke and improved mouse neurological functions. Our study provides a strategy to inhibit neuroinflammation using neutrophil-derived nanovesicles for ischemic stroke therapy.

Advanced Functional Materials and Cell‐Based Therapies for the Treatment of Ischemic Stroke and Postischemic Stroke Effects

“…Based upon this, exosomes derived from mesenchymal stem cells from embryos, bone marrow, and adipose tissue have been reported. In these studies, exosomes were loaded with various therapeutics, including antioxidants such as curcumin and the pigment epithelium‐derived factor (PEDF), or small noncoding RNAs such as the miR‐124 82b. In the cases of the antioxidant therapeutics, amelioration of the postischemic stroke effects was achieved by repression of apoptosis and regulation of inflammation through the inhibition of proinflammatory cytokines' production.…”

“…On the other hand, the delivery of miR‐124 led to enhanced cortical neurogenesis that was demonstrated by the increase in SOX2 (sex‐determining region Y‐box 2) and nestin markers. Although exosomes exhibit targeting abilities toward autologous cell types, functionalization with various targeting groups such as the cyclo (Arg‐Gly‐Asp‐ d ‐Tyr‐Lys) peptide [c(RGDyK)]82a or proteins such as the rabies virus glycoprotein (RvG) fused with an exosomal protein lysosome‐associated membrane glycoprotein 2b (Lamp2b)82b have also been used aiming at improving their accumulation in ischemic tissues.…”

“…In a different approach, neutrophils were used to fabricate nanovesicles able to target the ischemic brain . It was demonstrated that the neutrophil‐derived nanovesicles could specifically target the ischemic lesion through integrin β2 and P‐selectin glycoprotein ligand‐1 (PSGL‐1).…”

Plasmonic Cell‐Derived Nanocomposites for Light‐Controlled Cargo Release inside Living Cells

“…Such biomimetic interfaces have thus emerged to overcome critical drawbacks inherent to synthetic nanomaterial‐based nanomedicines 9. Cell membrane‐derived nanoplatforms have proven to be remarkably effective for 1) targeting inflamed tissues such as inflamed endothelium involved in some neurological diseases (e.g., ischemic stroke) by using neutrophil membrane coatings10 or chronic inflammatory tumor tissue driven by macrophage coating,11 2) approaching vascular disorders (e.g., atherosclerosis) by using platelet coatings,12 and 3) developing personalized tumor nanovaccines against different tumor types by using tumor‐associated antigens from cancer cell‐derived coatings 13…”

Overexpression of Myocardin-related transcription factor-A attenuated middle cerebral artery occlusion/reperfusion-induced apoptosis via the Mcl-1/Cyt C/cleaved caspase 3 pathway

“…1,2 The immediate restoration of blood supply to ischemic sites can reduce infarct volume and alleviate cognitive dysfunction. However, this causes secondary tissue damage, referred to as ischemia/reperfusion (I/R) injury, 3 which is an important cause of adverse prognosis after recanalization treatment in ischemic stroke patients. 4 Therefore, prevention and treatment strategies that are e®ective in reducing brain damage from cerebral I/R injury must be established.…”