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.

Inflammation and Acinar Cell Dual-Targeting Nanomedicines for Synergistic Treatment of Acute Pancreatitis via Ca2+ Homeostasis Regulation and Pancreas Autodigestion Inhibition

“…26−28 The efficacy of biomimetic neutrophil membrane-camouflaged NPs to target an inflammatory region via their biointerface properties of cell membranes has been reported in several studies, such as receptor-mediated adhesion of neutrophil-like polymeric NPs with cytokine-activated injured joint inflammation sites, 29 enhanced local targeting of biomimetic neutrophil membrane-coated gelled cores to an injured myocardium, 30,31 specific targeting of neutrophil membrane-enveloped polymeric NPs toward the renal ischemia-reperfusion injury region, 32 and the active targeting effects of neutrophil membrane-coated nanozymes toward damaged brain sites. 33,34 There is limited research on the utilization of neutrophil membrane-wrapped nanocarriers for enhancing drug delivery to the pancreas or damaged acinar sites. During AP, neutrophils adhere to active endothelial cells through membrane adhesion proteins, such as integrin β2 on neutrophils and ICAM-1 expressed on the endothelium, and migrate further across endothelial junctions, guided by chemokine gradients.…”

“…The membrane coating strategy provides a straightforward approach to designing biomimetic cell membrane-coated NPs with surfaces that inherently mimic the properties of the source cells, bestowing them to replicate natural cellular interactions, leading to enhanced biocompatibility, immune evasion, long circulation, and disease-relevant targeting. As the most rapid and aggressive immune cells in response to an inflammatory insult, circulating neutrophils are typically the initial leukocytes to be recruited. − The efficacy of biomimetic neutrophil membrane-camouflaged NPs to target an inflammatory region via their biointerface properties of cell membranes has been reported in several studies, such as receptor-mediated adhesion of neutrophil-like polymeric NPs with cytokine-activated injured joint inflammation sites, enhanced local targeting of biomimetic neutrophil membrane-coated gelled cores to an injured myocardium, , specific targeting of neutrophil membrane-enveloped polymeric NPs toward the renal ischemia-reperfusion injury region, and the active targeting effects of neutrophil membrane-coated nanozymes toward damaged brain sites. , There is limited research on the utilization of neutrophil membrane-wrapped nanocarriers for enhancing drug delivery to the pancreas or damaged acinar sites. During AP, neutrophils adhere to active endothelial cells through membrane adhesion proteins, such as integrin β2 on neutrophils and ICAM-1 expressed on the endothelium, and migrate further across endothelial junctions, guided by chemokine gradients.…”

Sulfated Polysaccharide-Based Nanocarrier Drives Microenvironment-Mediated Cerebral Neurovascular Remodeling for Ischemic Stroke Treatment

“…The microglia, a cohort of immune cells that inhabit the central nervous system (CNS), primarily assume the pivotal roles of safeguarding the host, modulating inflammation, and facilitating functional recovery after ischemic stroke . After blood reperfusion, the rapid generation of ROS triggers microvascular dysfunction and microthrombus formation, subsequently leading to the clustering and activation of microglia around injured brain capillaries through the interaction between fibrin and microglial integrin receptors. , The activation of microglia serves as the initial response to a stroke event, displaying remarkable heterogeneity and possessing the ability to adapt to their surrounding microenvironment, thereby secreting cytokines that effectively regulate angiogenesis, myelin regeneration, and neuronal remodeling . Therefore, regulating microglial activity with biomaterials offers a promising approach to enhance multicell coupling in the pathological microenvironment of stroke and effectuate optimal therapeutic outcomes.…”