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Type 2 diabetes mellitus (T2DM) poses a significant global health challenge, highlighting the urgent need for effective therapeutics. Heterophyllin B (HB), a cyclic peptide derived from Pseudostellaria Radix, has been proposed as a promising drug for T2DM. In this study, we systematically verified that HB could alleviate T2DM by modulating the hepatic IRS2/PI3K-Akt/FoxO1 signaling pathway, restoring bile acid and glycerophospholipid metabolism. However, the therapeutic potential of HB is hampered by its poor solubility, low oral bioavailability, and susceptibility to P-glycoprotein (P-gp) efflux. To overcome these limitations, we developed an oral delivery system in which a N-acetylgalactosamine (GalNAc)-modified pillar[6]arene (P6) designed for liver targeting encapsulates HB and then incorporated into a mucoadhesive interpolymer complex (IPC) micropatch, namely HB ⊂ P6-GalNAc/IPC. The formulation was encapsulated in enteric capsules for oral administration, which significantly enhanced intestinal absorption of HB and achieved a high oral bioavailability of 66.31%, approximately 3.3 times that of free HB. This improvement was attributed to multiple mechanisms, including reversible tight junction opening, inhibition of P-gp efflux, and activation of both clathrin- and caveolae-mediated endocytosis. In a high-fat diet/streptozotocin (HFD/STZ)-induced T2DM mouse model, HB ⊂ P6-GalNAc/IPC formulation outperformed metformin in improving glycemic control, insulin sensitivity, and lipid metabolism, while also ameliorating hepatic steatosis and providing notable pancreatic and renal protection. Collectively, this work not only clarifies the anti-diabetic mechanisms of HB but also offers a versatile strategy for the effective oral delivery of peptide-based therapeutics.