Synergistic Delivery of Probiotics and Polyphenol Nanoparticles by Inulin Hydrogel for Alleviating Type 2 Diabetes Mellitus

ABSTRACT Type 2 diabetes mellitus (T2DM), a systemic metabolic network disorder, demands multiorgan intervention to restore homeostasis, posing a major global health burden. Concurrent instant glycemic control and long‐term microbiota remodeling represent an urgent scientific challenge. Herein, an inulin (INU) and hyaluronic acid (HA) double network hydrogel (IHGel) is presented to co‐deliver Bifidobacterium longum (BL) and lactoferrin (LF)‑Zn‑epigallocatechin gallate (EGCG) ternary nanoparticles (LZE NPs). The obtained LZE/BL@IHGel as an oral composite platform exhibits acid‑induced protonation to generate pH responsive pore shrinkage in the stomach, which results in protective effects of BL and sustained release of LZE NPs. Furthermore, LZE NPs maintain stable free radical scavenging activity and α ‐glucosidase inhibitory activity via metal–polyphenol coordination assembly and enhance cellular uptake through protein incorporation, thereby alleviating intestinal oxidative stress and controlling postprandial glucose. In a murine model of T2DM, 6 weeks of daily oral LZE/BL@IHGel demonstrated spatiotemporal separation of acute glycemic control and long‑term microbiota modulation by ameliorating glucolipid metabolism and multi‑organ complications, restoring intestinal homeostasis. Collectively, this study offers a versatile oral delivery strategy to bridge immediate glycemic control with long‑term gut remodeling, providing a new avenue for complex metabolic disease intervention.