Mitochondrial Protection and Neural Repair via ROS‐Responsive Biomimetic Nanoparticles in Intracerebral Hemorrhage

Intracerebral hemorrhage (ICH)‐induced secondary brain injury is driven in part by oxidative stress, blood‐brain barrier disruption, mitochondrial dysfunction, and neuronal loss. Here, we developed a brain endothelial cell membrane‐coated ROS‐responsive biomimetic nanoplatform (NP@D+M) for co‐delivery of the VDAC1 inhibitor DIDS and the mitochondrial fission inhibitor Mdivi‐1. NP@D+M showed uniform size, preserved endothelial membrane proteins, and accelerated drug release under elevated H2O2. In ICH‐like neuronal injury models, NP@D+M enhanced uptake, protected neurites, reduced LDH release and apoptosis, restored mitochondrial membrane potential and ATP production, and suppressed mitochondrial ROS. Mechanistically, NP@D+M disrupted aberrant LPAR1‐VDAC1 interaction, inhibited mPTP opening, and restored mitochondrial homeostasis; LPAR1 gain‐ and loss‐of‐function experiments confirmed its role in the mitochondrial protective effect. Targeted metabolomics and single‐cell transcriptomics further supported improved energy metabolism and attenuated injury‐associated cellular responses. In vivo, NP@D+M crossed the BBB, accumulated in brain parenchyma, protected perihematomal neurons, improved mitochondrial function, and alleviated neurological and cognitive deficits without obvious systemic toxicity. These findings identify a LPAR1‐VDAC1‐mPTP‐targeted nanotherapeutic strategy for mitochondrial protection and neural repair after ICH.