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 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 AlCl 3 /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 nanoparticles (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.