1. Research and Highlights
Impaired mitophagy and the accumulation of damaged mitochondria are key drivers of endothelial cell (EC) dysfunction in diabetic wounds. While mitochondrial transplantation (MT) has demonstrated therapeuticpotential in such mitochondrial damage-related diseases, its application is still thwarted by elusive mechanisms and practical hurdles such as poor targeting specificity and low delivery efficiency. Here, wereveal that MT acts by reactivating mitophagy to selectively eliminate dysfunctional mitochondria, therebyrestoring mitochondrial homeostasis and rescuing EC functionality. To exploit this discovery, we engineer abiomimetic MT strategy through coating EC-derived apoptotic vesicle membrane (AVM) onto the surfaceof isolated mitochondria. The resulting mitochondria–AVM complex (Mito-AVM) leverages homologoustargeting and phosphatidylserine-mediated “eat-me” signaling, achieving a remarkable 150% increasein delivery efficiency to ECs in diabetic wounds. Furthermore, we construct a 3-aminophenylboric acid-modified hyaluronic acid/polyvinyl alcohol hydrogel for the diabetic wound microenvironment, enablingreactive oxygen species/glucose-triggered sustained release of encapsulated Mito-AVM at the wound site. In summary, our work elucidates a fundamental mechanism of MT and provides an efficient and targetedstrategy for MT therapy, offering fresh perspectives for diabetic wound treatment.
The research findings have been published in Research under the title "Apoptotic Vesicle Membrane-Mediated Targeted Endothelial Mitochondrial Transplantation-Clearance Therapy for Diabetic Wound Healing."
Citation：Zheyuan Hu, Shutong Qian, Bo Liao, Yuhuan Wang, Qian Lu, Jiayi Mao, Bolun Lu, Liucheng Zhang, Fei Wang, Danru Wang, et al. Apoptotic Vesicle Membrane-Mediated Targeted Endothelial Mitochondrial Transplantation-Clearance Therapy for Diabetic Wound Healing. Research. 2026;9:1042.DOI:10.34133/research.1042
2. Significance and Innovative Findings
This study mechanistically validates that mitochondrial transplantation repairs endothelial cell function via mitophagy. Furthermore, it proposes and validates for the first time an integrated "Targeted Endothelial Mitochondrial Transplantation-Clearance Therapy". The research ingeniously utilizes apoptotic cell-derived vesicle membranes as a biomimetic carrier, co-loading mitochondria to construct an intelligent biomimetic delivery system (Mito-AVM).
The core advantages of this system are:
- High-Efficiency Targeting: The apoptotic vesicle membrane, derived from endothelial cells, contains surface homologous targeting proteins as well as "find-me" and "eat-me" signals, enabling it to efficiently target and be endocytosed by vascular endothelial cells at the wound site (Figure 2A). The apoptotic vesicle membrane is prepared by subjecting apoptotic vesicles to hypo-osmotic and ultrasonic treatment to remove their contents (Figures 2B, C). Mito-AVM is obtained by gently mixing the apoptotic vesicle membrane with mitochondria followed by intermittent ultrasound for 5 minutes (Figure 2D). The prepared Mito-AVM demonstrates excellent targeting ability and high efficiency in delivery to endothelial cells (Figures 2E, F).
- Precise Autophagy: Within the target cells, the released mitochondria activate mitophagy (Figure 3A). TEM observations revealed the clearance of damaged mitochondria (Figure 3B), along with increased co-localization of mitochondria with LC3 and lysosomes (Figures 3C, D). This process reduces the sustained release of intracellular ROS, restores normal mitochondrial function, directly enhances cellular energy metabolism and activity, and fundamentally reshapes the cellular energy homeostasis.
- Smart Application: Mito-AVM is loaded into an HA-PBA/PVA hydrogel, enabling glucose/ROS dual-responsive intelligent release at the diabetic wound site. Animal experiments demonstrate that this system significantly promotes angiogenesis and collagen deposition, accelerating wound healing in diabetic model mice, with efficacy markedly superior to any single therapy.
This work provides a novel concept and a powerful tool for organelle-based precision medicine, upgrading the classical "mitochondrial transplantation" into an intelligent, targeted, and efficient "transplantation-clearance" therapeutic system.
3. Future Perspectives
This research not only offers a highly translatable new technology for treating diabetic chronic wounds but also presents a biomimetic delivery and organelle therapy strategy with broad applicability. In the future, this platform technology holds promise for application in other diseases closely associated with mitochondrial dysfunction, such as myocardial ischemia-reperfusion injury and neurodegenerative disorders. Furthermore, by modifying the carrier membrane type or payloads, this strategy can be extended to the precise regulation of other organelles (e.g., lysosomes, nucleus), opening up broader prospects for regenerative medicine and disease therapy.
The complete study is accessible via DOI:10.34133/research.1042