Layered glycoprotein nanoparticles co-delivering Meretrix meretrix-derived peptide and astaxanthin attenuate...

Marked differences in solubility and stability between hydrophilic bioactive peptides and hydrophobic carotenoids constrain their synergistic oral delivery. Building on the complementary activities of Meretrix meretrix-derived immunomodulatory peptide (MMIP) and astaxanthin (AST), this study developed co-loaded nanoparticles, HLC₁₀, featuring a BSA-dextran glycoprotein core and a composite outer layer of hyaluronic acid (HA) and yeast β-glucan. Hydrogen bonding, hydrophobic interactions, and electrostatic forces collectively drive the multicomponent assembly. By tuning particle interfacial hydration and the dispersion state of the payloads, the formulation improved co-encapsulation capacity, processing and storage stability, and gastrointestinal bioaccessibility of MMIP and AST. The composite polysaccharide outer layer further increased particle accumulation in Peyer's patches-associated regions and increased uptake by RAW264.7 macrophages. Oral HLC₁₀ administration ameliorated cyclophosphamide-induced immunosuppression, restored immune organ and ileal architecture, and produced coordinated shifts in gut microbiota, fecal short-chain fatty acids, and spleen nucleotide-related metabolic profiles. These findings support the immunomodulatory potential of HLC₁₀, but the evidence remains largely limited to endpoint measures in animal models, and direct validation of cellular functions and the underlying mechanisms is still required. Overall, this stratified co-assembly strategy offers a feasible route for the synergistic oral delivery of food-derived active ingredients with markedly different physicochemical properties.