Mitochondrial micro-nano reactors via enhancing mitochondrial transfer and mitophagy for alleviating metabolic crisis

Energy metabolic dysfunction is a major cause of impaired chronic wounds healing, in which disrupted mitochondrial transfer and autophagy imbalance further aggravate the cellular energy crisis. In this study, single-cell RNA sequencing (scRNA-seq) of clinical diabetic wound samples first identified a pivotal role for macrophage-to-fibroblast mitochondrial transfer in wound healing. This finding was further validated using diabetic wound models and histological analyses, highlighting these processes as potential therapeutic targets for alleviating energy metabolic stress. Based on these findings, we innovatively developed a mitochondrial micro-nano reactor (MtNR) that alleviates the energy metabolic crisis by concurrently enhancing mitochondrial transfer and autophagy. First, hypoxic-preconditioning combined with gene-edited techniques was used to generate M2 macrophage-derived mitochondria-trained apoptotic bodies (mABs). Subsequently, mABs were conjugated with piezoelectric short fibers (PSFS) via copper-free strain-promoted azide-alkyne cycloaddition (SPAAC) click chemistry to self-assemble into MtNR. This system promotes intercellular mitochondrial transport through the Miro1-mitochondria-dynein-microtubule complex. It also generates bionic electrical signals via mechano-electrical conversion, thereby restoring Pink1-Parkin-P62/SQSTM1-LC3-mediated mitophagy and mitochondrial homeostasis. In a diabetic mouse wound model, MtNR restored mitochondrial morphology, enhanced cellular energy biogenesis, reduced p62 accumulation, increased LC3 expression, and significantly promoted tissue repair, providing a promising therapeutic strategy for addressing the energy deficit in diabetic wounds.