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 H2S 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 H2S 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.