Intranasal Pathogenesis‐Adaptive Nanotherapeutics Reinstate Regenerative Competence for Post‐Stroke Neural Repair

ABSTRACT Poststroke neurorehabilitation is limited by the poor regenerative capacity of adult neurons. Although neural stem cells (NSCs) can generate new neurons, their reparative potential is constrained by inefficient delivery to cerebral lesions and a hostile regenerative niche. Here, analysis of a single‐nucleus transcriptomic dataset revealed pronounced dysfunction and intercellular crosstalk among neurons, microglia, and NSCs, highlighting redox imbalance and impaired nitric oxide (NO) signaling as potential therapeutic targets. Guided by these findings, we develop FCeO 2 @GLp, a pathogenesis‐adaptive nanotherapeutic integrating reactive oxygen species scavenging, NO replenishment and immune modulation within cerebral ischemic microenvironment. Following intranasal administration, FCeO 2 @GLp actively adheres to the olfactory epithelium (OE), reaches infarcted brain regions, releases cerium oxide (CeO 2 ) nanozyme, fingolimod, and a NO donor in response to local acidity. This coordinated strategy alleviates oxidative stress, reprograms microglia, protects neurons, and enhances NSC proliferation and neuronal differentiation. Consequently, FCeO 2 @GLp effectively reduces infarct volume and cerebral edema during the acute phase, and improves long‐term neurological function and survival, establishing a lesion‐responsive strategy for poststroke neural repair.