Cellulose-like chitosan microfibrils facilitate targeted release and enhance the prolonged residence time of quercetin-selenium nanoparticles for Alzheimer's disease treatment.

The effect of digestion on nanocarriers will affect the release and pharmacological effects of bioactive compounds in delivery systems. The digestion of cellulose is limited to gut microbiota, which offers a new research strategy for targeted delivery of bioactive compounds. Herein, positively charged cellulose-like chitosan/polyvinylpyrrolidone nanofiber was prepared to improve the residence time, colon target and gut microbiota regulation activity of quercetin decorated selenium nanoparticles (QUE@SeNPs/CS/PVPNFs). Selenium nanoparticles block the degradation of quercetin and QUE@SeNPs/CS/PVPNFs only decompose when caused by chitosanase secretion from gut microbiota. In vivo imaging showed that the residence time of QUE@SeNPs/CS/PVPNFs was longer than that of QUE@SeNPs. Thus, it significantly decreased the lipid concentrations in liver, which further inhibited insulin resistance in mice. Moreover, QUE@SeNPs/CS/PVPNFs treatment improves gut barrier integrity, increased the relative abundance of anti-obesity and anti-inflammation related bacterial including Akkermansia, Lactobacillus and Bacteroides. Consequently, the inflammatory factor (IL-β and TNF-α) levels in gut, liver and brain were also decreased. Nissl and PSD-95 staining indicated that QUE@SeNPs/CS/PVPNFs ameliorated synapse dysfunction in the brain. Therefore, QUE@SeNPs/CS/PVPNFs has a greater effect than QUE@SeNPs in improving cognitive ability in Morris water maze. Overall, QUE@SeNPs/CS/PVPNFs with prolonged residence time attenuates cognitive disorder via gut-liver-brain axis in AD.