Mannan-oligosaccharides-based self-assembly nanoparticles enable gut-specific quercetin release, providing multi-pathway protection against AD via gut-brain axis.

Mannan-oligosaccharides (MOS), as indigestible functional prebiotic, support intestinal health. Here, we engineered MOS to undergo linoleic acid (LA)-mediated self-assembly with quercetin, forming lipid bilayer nanoparticles (MOS-LA/LA-Q NPs). These nanoparticles (NPs) achieved a high quercetin encapsulation efficiency (92.4%) and demonstrated superior stability in aqueous solution at 4 °C. The MOS outer layer effectively protected the quercetin core from gastrointestinal stress. Triggered by microbial enzymes, the system enabled a sustained quercetin release, up to 60% over 48 h, representing a novel microbe-specific delivery mechanism. In an Alzheimer's disease (AD) mice models induced by AlCl3/D-galactose, MOS-LA/LA-Q NPs significantly enhanced gut microbiota diversity, restored gut microbiota balance, suppressed pathogenic bacteria, and regulated metabolites short-chain fatty acid (SCFA) and lactic acid levels. Compared with free quercetin, these NPs alleviated cognitive deficits, reduced inflammation and oxidative stress in both the colon and brain, improved gut-brain barrier integrity, and restored gut-brain function more significantly. Mechanistically, these effects were associated with modulation of the Kelch-like ECH-associated protein 1 (Keap1)/nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) and toll-like receptor 4 (TLR4)/nuclear factor kappa-B (NF-κB) pathways, reducing tau phosphorylation and Aβ amyloid levels, thus demonstrating superior neuroprotection. This study proposes a novel strategy for addressing the complex pathology of AD through multi-target intervention, highlighting the potential of MOS-based NPs to enhance quercetin's therapeutic efficacy.