pH-responsive Oral liposomal delivery of hydrogen sulfide donor GYY4137 enables colon-targeted therapy for inflammatory bowel disease

Background Although therapeutic options for inflammatory bowel disease (IBD) have advanced, many patients still experience suboptimal clinical response, systemic side effects, or difficulty maintaining long-term treatment adherence. Hydrogen sulfide (H₂S), an endogenous gasotransmitter with potent anti-inflammatory and mucosal-protective properties, has shown promise as a therapeutic agent for IBD. However, clinical application has been constrained by its instability in low pH and the need for parenteral administration. Results Here, we report the first orally administered, pH-responsive liposomal formulation of the H₂S donor GYY4137, specifically designed for colon-targeted delivery. This system, termed oral hydrogen sulfide donor-loaded liposome (Oral H₂S lipo), employs a pH-sensitive Eudragit S100 coating that forms protective aggregates under acidic gastric conditions (pH 2) to shield the liposomes and suppress premature H₂S release. In this environment, Oral H₂S lipo limited cumulative release of H 2 S to 12.13% over 8 days, representing a ~ fivefold reduction compared to free GYY4137 (60% release). Upon exposure to colonic pH (≥ 7), the coating dissolved, restoring the native liposomal state as evidenced by a reduction in polydispersity index (PDI) from 0.777 to 0.076, and enabling sustained H 2 S release. The formulation also exhibited high drug loading efficiency (74.65%), stable physicochemical properties across gastrointestinal pH conditions for at least 14 days and excellent in vitro biocompatibility over a wide concentration range (0–120 μM). In vivo fluorescence imaging in a dextran sodium sulfate (DSS)-induced colitis model demonstrated that DiR-labeled Oral H₂S lipo achieved ~ 2.4-fold higher colonic accumulation than free DiR (p < 0.01) and ~ 1.7-fold higher than DiR-H₂S lipo (p < 0.05), validating the functionality of the pH-responsive coating for site-specific drug release. Therapeutic studies further showed improved colon length, reduced histological inflammation, and preservation of mucosal structure. Conclusions These findings demonstrate that Oral H₂S lipo enables effective, site-specific delivery of H₂S to inflamed colonic tissue, offering a clinically relevant platform to overcome limitations of conventional H₂S donor therapies in IBD management. Graphical abstract