Abstract
Precise regulation of mitochondrial reactive oxygen species (mtROS) in macrophages is essential for reducing inflammation and promoting diabetic wound healing. However, achieving targeted and responsive mtROS modulation in specific cell remains challenging. Herein, we report a macrophage-mitochondria hybrid membrane derived artificial extracellular vesicle platform (C@AH-EV). C@AH-EV integrates biomimetic dual-targeting membranes with an mtROS activatable prodrug. It leverages membrane protein-mediated targeting of macrophage mitochondria to offer highly selective intracellular delivery. The payload is a ROS sensitive antioxidant prodrug, which incorporates lipid tails that enhance its drug loading efficiency in vesicles. Upon mtROS-triggered cleavage of the boronate ester bond, potent antioxidants were locally released within the mitochondria to restore redox balance. In vitro and in vivo studies demonstrate that C@AH-EVs effectively reprogram macrophages from an inflammatory toward an anti-inflammatory phenotype, thereby attenuating inflammation and accelerating diabetic wound repair. This work offers a promising direction for treating chronic inflammatory conditions.
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The data that support the findings of this study are available within the article and its Supplementary Information files. Source data are available for Figs. 2d–g, i, 3e, g–i, 5b, h, k, 6b, c, g, h, 7b, c, e, f, 8a–f and 9d, Supplementary Figs. 16, 19, 21, 22, 26–30 and 34–43. Source data are provided with this paper.
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Acknowledgements
This work was supported by the National Natural Science Foundation of China (Grant No. 82402908 to L.F., Grant No. 82372523 to J.T.H., Grant No. 62475216 to B.P., Grant No. 82272261 to X.K.Y.), Key Research and Development Program of Shaanxi (Grant No. 2024SF-ZDCYL-04-10 to H.G., Grant No. 2024GH-ZDXM-37 to B.P., Grant No. 2022JC-58, 2024SF-ZDCYL-03-26 to X.K.Y.), Shaanxi Province Health Science Research and Innovation Capacity Enhancement Project (Grant No. 2025PT-03 to H.G.).
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L.F. and C.H.Z. collaborated to complete the study and drafted the manuscript. Z.G.X., Z.L.L., and B.Z. assisted with the preparation of nanovesicles. H.L. and J.X.W. assisted with animal experiments. Z.W., J.T.H., and H.G. provided technical help for this study. B.P., N.H.V., and X.K.Y. reviewed and edited the manuscript. All authors discussed the results and implications and commented on the paper.
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Fan, L., Zhang, C., Xu, Z. et al. Hybrid macrophage-mitochondria extracellular vesicles for mitochondrial ROS regulation in diabetic wounds. Nat Commun (2026). https://doi.org/10.1038/s41467-026-69383-3
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DOI: https://doi.org/10.1038/s41467-026-69383-3
