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.