Cyclodextrin–polysaccharide nanocomposite improves the oral stability and antidiabetic efficacy of chlorogenic acid in type 2 diabetic mice

• Mucoadhesive CGA@CDs-HA-TMC nanoplatform enhances oral chlorogenic acid delivery • Nanocomposite improves CGA solubility, stability and sustained GI release. • CGA@CDs-HA-TMC improves glucose, lipids, inflammation and organ damage in T2DM. Type 2 diabetes mellitus (T2DM) is a major global health burden. Chlorogenic acid (CGA) shows antidiabetic potential by improving glucose/lipid metabolism, insulin sensitivity, and inflammatory/oxidative status, but its use is limited by poor solubility, low gastrointestinal stability, extensive first-pass metabolism, and low oral bioavailability. Here, we developed an oral multilayer nanodelivery system (CGA@CDs-HA-TMC) comprising cyclodextrin inclusion cores (CDs) and hyaluronic acid (HA) plus trimethyl chitosan (TMC) outer layers. The nanocomposites displayed a uniform nanoscale size, positive ζ-potential, and favorable colloidal dispersion characteristics. Spectroscopic and X-ray diffraction analyses confirmed CGA amorphization and stable encapsulation within the cyclodextrin–polysaccharide network. CGA@CDs-HA-TMC reduced burst release in simulated gastric fluid and enabled sustained release in simulated intestinal fluid. In high-fat diet/streptozotocin-induced T2DM mice, CGA@CDs-HA-TMC lowered fasting blood glucose and OGTT AUC, improved insulin resistance (HOMA-IR), and partially restored β-cell function (HOMA-β). It also improved dyslipidemia, decreased ALT, AST, serum creatinine, BUN, 24-h urinary protein, and reduced circulating TNF-α, IL-6, IL-1β, and IL-18, generally outperforming free CGA. Histology further showed alleviation of hepatic steatosis, renal glomerular/tubular injury, and pancreatic islet damage. Overall, CGA@CDs-HA-TMC is a promising cyclodextrin–polysaccharide nanoplatform for enhancing oral delivery and antidiabetic efficacy of CGA and other poorly bioavailable polyphenols.