Bifunctional Nanostarch against Neuronal Apoptosis via Mitochondria Protection for Ameliorating Ischemic Stroke Injury and Promoting Long-Term Neurological Recovery

Mitochondrial damage occurs as an initial event following ischemic onset, and the extent of mitochondrial dysfunction is highly correlated to the severity of ischemia-induced cell death. Once appropriate therapeutic interventions are provided, the ischemic tissue can be salvaged, which is of great significance in achieving better neurological outcomes. Herein, we developed a nanosized starch as a targeting nanoplatform, featuring effective blood-brain barrier (BBB) penetration through lactoferrin-mediated transcytosis. Notably, the nanostarch-based delivery of Mdivi-1 and Alda-1 enables controlled release in the acidic lysosome of neurons, effectively inhibiting the pathological mitochondrial fission and metabolizing toxic aldehydes, thereby creating protective effects on maintaining mitochondrial function. Moreover, we demonstrated that mitochondrial protection induces a transition from activated pro-death responses to a pro-survival state by reducing the release of pro-apoptotic proteins, significantly contributing to the long-term recovery of neurological function. Overall, our nanostarch provided an in-depth understanding of the delivery of mitochondrial protectants and underscored the potential and utility of mitochondrial protection for ischemic stroke via minimizing neuronal apoptosis.