Intranasally Delivered Echinacoside Micelles Modulate Mitochondrial Fusion Against Postoperative Cognitive Dysfunction

Abstract The disruption of mitochondrial homeostasis in neurons accounts for the onset and progression of postoperative cognitive dysfunction (POCD). Echinacoside (ECH) can facilitate mitochondrial fusion to mediate neuroprotection, but its therapeutic efficacy is greatly limited by inefficient brain accumulation and neuronal delivery. Herein, ECH‐encapsulated micelles are constructed from the copolymer containing the poly(carboxybetaine methacrylate) (PCBMA) block and phenylboronic acid (PBA)‐modified poly(dimethylamino)ethyl methacrylate block, which mediates effective, brain‐targeted delivery via intranasal administration. In POCD mice, the micelles efficiently penetrate nasal mucosa via the betaine structure in PCBMA that can be recognized by betaine‐GABA transporter 1 (BGT‐1) on nasal epithelial cells, followed by the accumulation into the hippocampus through the submucosal olfactory and trigeminal nerve pathways. Subsequently, the micelles are efficiently internalized by neurons via BGT‐1‐mediated endocytosis. The over‐produced reactive oxygen species inside neurons trigger micelles dissociation and ECH release, thereby inducing mitochondrial fusion to enhance neuron survival, ameliorate cerebral microenvironment, and restore cognitive and memory functions. This study reports a non‐invasive strategy to overcome the physiological barriers against cerebral drug delivery and renders profound implications for POCD treatment.