Bioinspired nanoerythrocytes for metabolic microenvironment remodeling and long-term prognosis promoting of acute ischemic stroke

Metabolic microenvironment dysfunction remains hallmarks of acute ischemic stroke (AIS) throughout the ischemia, reperfusion, and recovery stages. Existing therapeutic strategies focus only on a single pathological process, while cascading metabolic changes are neglected. For the sake of better long-term prognosis, interventions in each stage are certainly worthwhile if achievable. Herein, inspired by the natural hemoglobin (Hb) carrying oxygen mechanism, a polymer-based nanoerythrocyte is designed to remodel the metabolic microenvironment in the whole stages of AIS. Briefly, Hb and methoxatin are incorporated into polydopamine nanocage which is further coated with the polymer layer formed by in-situ free radical polymerization. Modified with microthrombus-targeting peptide, this nanoerythrocyte can actively accumulate in the ischemic core and respond to the metabolic microenvironment. In vivo results demonstrate that cellular metabolic homeostasis and responsiveness are restored by oxygen balance regulation, microglia polarization, glucose metabolism activation, and neovascularization in permanent and transient middle cerebral artery occlusion model mice. The behavioral experiment results also confirm the effects of nanoerythrocyte for long-term prognosis. This strategy gives a proof of concept that metabolic microenvironment modulation is a promising perspective for AIS treatment with nanoerythrocytes.