Multifunctional Selenium Nanoparticles with Different Surface Modifications Ameliorate Neuroinflammation through the Gut Microbiota-NLRP3 Inflammasome-Brain Axis in APP/PS1 Mice

Neuroinflammation plays a critical role in Alzheimer's disease (AD). However, it is still unknown if neuroinflammation can be effectively treated using selenium nanoparticles (SeNPs) with different surface modifications. In this study, SeNPs were coated with dihydromyricetin (DMY), a natural polyphenol, to obtain DMY@SeNPs. Given that DMY@SeNPs are unstable under physiological conditions, they were decorated step-by-step with chitosan (CS/DMY@SeNPs) and with the blood brain barrier (BBB) targeting peptide Tg (TGNYKALHPHNG) to yield Tg-CS/DMY@SeNPs, which significantly reduced the aggregation of Aβ and improved the anti-inflammatory effects of SeNPs in vitro. The mechanisms of CS/DMY@SeNPs and Tg-CS/DMY@SeNPs on regulating neuroinflammation are different. Only Tg-CS/DMY@SeNPs can cross the BBB; therefore, Tg-CS/DMY@SeNPs more successfully inhibited Aβ aggregation and reduced inflammatory cytokine secretion via the NF-κB pathway in the brain of APP/PS1 mice compared to CS/DMY@SeNPs. Furthermore, both types of nanoparticles, however, were able to repair the gut barrier and regulate the population of inflammatory-related gut microbiota such as Bifidobacterium, Dubosiella, and Desulfovibrio. Of note, the relative abundance of Gordonibacter was only enhanced by Tg-CS/DMY@SeNPs, thereby downregulating the protein expression of the NLRP3 inflammasome and the concentrations of serum inflammatory factors. This demonstrates that Tg-CS/DMY@SeNPs ameliorate neuroinflammation through the gut microbiota-NLRP3 inflammasome-brain axis. Overall, our data suggest that Tg-CS/DMY@SeNPs are an ideal drug candidate for AD treatment.