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Nanoparticles are primarily taken up by immune cells after systemic administration. Thus, they are considered an ideal drug delivery vehicle for immunomodulation. Because the spleen is the largest lymphatic organ and regulates the systemic immune system, there have been studies to develop spleen targeting nanoparticles for immunomodulation of cancer and immunological disorders. Inflammatory bowel disease (IBD) includes disorders involving chronic inflammation in the gastrointestinal tract and is considered incurable despite a variety of treatment options. Hydrogen sulfide (H 2 S) is one of the gasotransmitters that carries out anti-inflammatory functions and has shown promising immunomodulatory effects in various inflammatory diseases including IBD. Herein, we developed a delicately tuned H 2 S donor delivering liposome for spleen targeting (ST-H 2 S lipo) and studied its therapeutic effects in a dextran sulfate sodium (DSS) induced colitis model. We identified the ideal PEG type and ratio of liposome for a high stability, loading efficiency, and spleen targeting effect. In the treatment of the DSS-induced colitis model, we found that ST-H 2 S lipo and conventional long-circulating liposomes loaded with H 2 S donors (LC-H 2 S lipo) reduced the severity of colitis, whereas unloaded H 2 S donors did not. Furthermore, the therapeutic effect of ST-H 2 S lipo was superior to that of LC-H 2 S lipo due to its better systemic immunomodulatory effect than that of LC-H 2 S lipo. Our findings demonstrate that spleen targeting H 2 S lipo may have therapeutic potential for IBD.