Nature‐Inspired Surface Modification Strategy Reverses the Autophagic Flux Impairment of Mitochondrial Transplantation for Attenuating Ischemic Strokes

ABSTRACT Mitochondrial transplantation has emerged as a promising therapeutic intervention for ischemic strokes (IS). Although previous studies have demonstrated the therapeutic breakthroughs of mitochondrial transplantation facilitated by advances in biotechnology, in‐depth investigations into the exact mechanisms underlying its beneficial effects remain insufficient. Here, we investigate how exogenous mitochondria interact with recipient cells to optimize therapeutic protocols and improve outcomes. Emerging evidence indicates that exogenous mitochondria act as triggers of mitophagy via the PTEN‐induced putative kinase 1 (PINK1)–Parkin pathway. However, excessive reactive oxygen species (ROS) generated during ischemia‐reperfusion injury activate the receptor‐interacting protein (RIP)1/RIP3 pathway, leading to the blockage of autophagic flux. Hence, we devised a novel mitochondrial transplantation platform (MLSR) that utilizes functionalized starch as a stable coating for exogenous mitochondria and enables the co‐delivery of the antioxidant resveratrol through the helical structure of the starch. Following internalization by recipient neurons, the exogenous mitochondria rapidly initiate mitophagy, while resveratrol escapes from the lysosome to inhibit the ROS‐RIP1/RIP3‐exosome axis. Experimental results demonstrate that MLSR effectively triggers and maintains positive autophagic flux, thereby suppressing the release of undegraded autophagosomes in the form of exosomes and preventing proinflammatory crosstalk between neurons and microglia. Therefore, our findings provide important implications for renewing the therapeutic potential of mitochondrial transplantation.