Abstract

The oral delivery of bioactive compounds for obesity management is severely hampered by their low bioavailability and lack of targeted release. To address this, we engineered a V-type single-helix starch (HAMS) via guest-directed molecular assembly as an advanced oral delivery platform. This system features well-defined nanocavities (~1.2 nm) that achieved 90.7% encapsulation efficiency for hydrophobic polyphenols (e.g., quercetin) and provided robust protection against gastrointestinal degradation. The crystalline architecture enabled enzyme-responsive dissociation, yielding a sustained polyphenol release profile and a 4.3-fold enhancement in systemic bioavailability compared to conventional carriers. In a diet-induced obesity mouse model, the HAMS-polyphenol co-assembly (HAMS-QP) elicited multifaceted therapeutic effects: it significantly mitigated body weight gain, dyslipidemia, glucose intolerance, and hepatic steatosis. Crucially, HAMS-QP restored gut barrier integrity, as evidenced by enhanced expression of tight junction proteins (ZO-1, occludin) and mucin-2, and alleviated chronic inflammation. Mechanistic studies revealed that these benefits were mediated through the suppression of PI3K-AKT pathway overactivation. Furthermore, HAMS-QP functioned as a potent prebiotic, selectively enriching beneficial gut microbiota (e.g., Lactobacillus , Akkermansia ) and boosting the production of protective short-chain fatty acids, particularly butyrate. Collectively, our work presents HAMS as a versatile and efficacious biomaterial that integrates precise encapsulation, controlled release, and host-microbe crosstalk into a single therapeutic strategy for metabolic disorders via the gut-metabolism axis.