Hybrid membrane-coated Cyclosporine A nanocrystals preventing secondary brain injury via alleviating neuroinflammatory and oxidative stress

Secondary brain injury (SBI), a prevalent complication following traumatic brain injury, remains a critical clinical challenge due to the lack of effective therapeutic interventions. Mitochondrial dysfunction in injured neurons and microglia has been identified as a pivotal driver of SBI pathogenesis. Cyclosporine A (CsA) exerts neuroprotective effects by inhibiting the over opening of the mitochondrial permeability transition pore, thereby preserving mitochondrial dysfunction in both neurons and microglia. These properties render CsA a promising candidate for SBI treatment. However, CsA shows systemic distribution and insufficient central nervous system penetration. In this study, a biomimetic SBI-targeted CsA nanocrystal system (CsA-NC@M_-PB) was prepared by using hybrid membranes derived from platelets and microglia. A large amount of CsA-NC@M_-PB actively accumulated in the damaged brain tissue in mild SBI mice. Mechanistically, CsA-NC@M_-PB effectively attenuated mitochondrial dysfunction in both neuron and microglia, and promoted microglial polarization towards M2 phenotype by suppressing the overproduction of reactive oxygen species. Meanwhile, by suppressing neuroinflammation and enhancing the integrity of the BBB, CsA-NC@M_-PB protected neuron from apoptosis and improved directional learning and memory abilities of mild SBI mice. These findings collectively demonstrated that CsA-NC@M_-PB was a therapeutically viable strategy for SBI management.