Introduction: Cerebral ischemia/reperfusion injury is the major cause of disability and death in ischemic stroke. However, there are currently almost no effective treatments for ischemia/reperfusion injury, a situation largely related to the lack of effective targeted therapeutic approaches and targets. To address this, we engineered MABs-DA1@PEG, a reactive oxygen species (ROS)-responsive apoptotic vesicle system that delivers the DA1 peptide to regulate the ATAD3A–Drp1 axis and restore mitochondrial quality control in ischemia/reperfusion injury, thereby reducing infarct volume and improve functional recovery. Methods: MABs-DA1@PEG was fabricated through acoustic perforation-mediated drug loading followed by thioketal (TK)-based ROS-responsive PEG modification. Physical properties and biosafety were assessed both in vivo and ex vivo. ROS-induced de-PEGylation kinetics and targeting specificity were quantified. Neuroprotection, anti-inflammatory effects, and mitochondrial quality control mechanisms were evaluated using a mouse middle cerebral artery occlusion/reperfusion (MCAO/R) model and an in vitro microglial oxygen-glucose deprivation/reperfusion (OGD/R) model. Results: MABs-DA1@PEG was engineered by encapsulating the mitochondrial quality-control peptide DA1 within macrophage-derived apoptotic bodies (MABs) and conjugating TK-linked PEG chains to their surface (Figure 1). The ROS-responsive de-PEGylation, targeting specificity, and biosafety of MABs-DA1@PEG was confirmed (Figure 2). After delivery, MABs-DA1@PEG accumulated at the ischemia/reperfusion injury region via PEG-mediated stealth properties and MABs-driven homing. Under the high ROS conditions present at the injury site, PEG detachment triggered the release of MABs-DA1, which were subsequently phagocytosed by microglia. This enabled specific delivery of the DA1 peptide into microglia within the ischemia/reperfusion region. By modulating the ATAD3A–Drp1 axis, the DA1 peptide restored mitochondrial quality control in microglia, thereby reducing infarct volume and promoted neurological recovery (Figure 3). Conclusions: MABs-DA1@PEG enables precise delivery to microglia within the ischemia/reperfusion region of ischemic stroke, where controlled DA1 release modulates the ATAD3A–Drp1 axis to restore mitochondrial quality control. This nanoplatform holds promise as a therapeutic strategy for ischemic stroke by precisely targeting molecular pathways in specific cell populations.
Wu et al. (Thu,) studied this question.