Agaricus bisporus chitosan modification improves the stability, intestinal retention, and hypoglycemic performance of metformin-encapsulated liposomes.

Gastrointestinal intolerance and limited intestinal residence remain important challenges in the long-term oral use of metformin (MET) for type 2 diabetes mellitus (T2DM). Although liposomal encapsulation can improve drug delivery, unmodified MET-encapsulated liposomes remain vulnerable to gastrointestinal disruption and premature leakage, which undermines their therapeutic potential. To address this limitation, Agaricus bisporus-derived chitosan (ACS) was employed as a bioactive macromolecular coating to construct MET-encapsulated liposomes (MET-LP). The ACS coating reversed the surface charge of MET-LP, improved colloidal dispersion, and enhanced storage stability, with 0.5% ACS-modified MET-encapsulated liposomes (A-M-L) retaining 83.1% encapsulation efficiency after 21 days at 4 °C. In T2DM mice, 1.0% A-M-L produced stronger glycemic control, lowering fasting blood glucose from 14.3 to 8.6 mmol/L, reducing HbA1c by approximately 32.9%, and decreasing the area under the curve (AUC) of the oral glucose tolerance test (OGTT) by 37.7%. Moreover, A-M-L improved serum lipid profiles and hepatic oxidative-stress-related indicators and was associated with lower ileal inflammatory cytokine levels and better-maintained gastrointestinal tissue morphology in T2DM mice. ACS modification also enhanced the intestinal retention of labelled liposomal carriers, as indicated by a 233.3% higher ileal fluorescence intensity of 0.5% A-M-L than unmodified MET-LP in SD rats. Collectively, these findings indicate that ACS modification improved the formulation stability, intestinal retention of labelled liposomal carriers, and hypoglycemic performance of MET-encapsulated liposomes.