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RVG29 and platelet membrane-modified pseudo-mitochondria for cascade targeting of cyclosporin a in traumatic brain injury.

Chenglu Hu,Yao Lin,Chengyuan Zhang,Jingyuan Yang,Minjie Lin,Yuanxu Cui,Yong Su,Xiangkang Jiang,Wenbin Zhang,Jiefeng Xu,Mao Zhang,Xing Zhou

Published 2025 in Journal of Controlled Release

ABSTRACT

Traumatic brain injury (TBI) is a major cause of mortality and morbidity worldwide. Cyclosporin A (CsA) is a promising drug for TBI, as it can protect neuronal mitochondria from dysfunction and apoptosis. However, CsA also has serious limitations, such as poor blood-brain barrier (BBB) penetration, non-selective distribution characteristic, and immunosuppressive effects. The latter is especially concerning, as TBI patients are highly susceptible to infections due to impaired immune function. Therefore, to realize the therapeutic potential of CsA for TBI, it is essential to achieve both efficient delivery of CsA to the injured brain and selective targeting of CsA to the neuronal mitochondria, while avoiding systemic immunosuppression. In this study, we borrowed from the fusion of mitochondria themselves and constructed pseudo-mitochondria based on the mitochondrial membrane. The pseudo-mitochondria successfully delivered the loaded substances to intracellular mitochondria by fusion with them. On this basis, we further achieved a cascade targeting delivery of CsA to injured neuron mitochondria in TBI through RVG29 and platelet membrane-modified pseudo-mitochondria, which significantly attenuated neuronal damage, neuroinflammation, and immunosuppression compared to CsA alone. Our study demonstrates the feasibility and potential of using RVG29 and platelet membrane-modified pseudo-mitochondria for cascade targeting of neuronal mitochondria in TBI therapy with CsA.

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