A Triple‐Role Nano‐Therapy by NADH@HMONs‐AAL for Precision Treatment of Cognitive Dysfunction Induced by Neuroinflammation through the Nose‐Brain Pathway

Abstract Sepsis‐associated encephalopathy (SAE) occurs in 70% of severely infected patients and the incidence rate of 17.7%. Previous studies have shown that Nicotinamide adenine dinucleotide (NADH) may treat nerve damage, but its inability to directly penetrate cell membranes limits its application. In this study, a nanoparticle (NADH@HMONs‐AAL) with one modification of triple‐role nano‐therapy is creatively prepared to treat SAE, and it is delivered to the brain through intranasal administration. There are three‐fold to introduce aleuria aurantia lectin (AAL) to modify the surface of NADH@HMONs. First, AAL adhered to HMONs as a mesoporous blocker to prevent drug leakage. Then, AAL increases the hydrophilic and hydrophobic properties of the nanoparticles, making NADH@HMONs more easily enter cells. Third, AAL allowed NADH@HMONs to bind to L‐fucose residues expressed on the olfactory epithelium, reducing clearance by cilia and effectively transporting NADH@HMONs‐AAL to the brain. This research indicates that NADH@HMONs‐AAL can directly enter the brain through intranasal administration and rapidly release NADH within cells. It repairs neuronal damage in the hippocampus and improves cognitive dysfunction in SAE‐induced cognitive neuroinflammatory mice. In conclusion, the nanoparticle prepared in this study using precision can alleviate the cognitive dysfunction caused by SAE, and provide a promising delivery route and method for treating neurological diseases.