We investigated oral delivery of transforming growth factor beta 1 [TGFβ]- and all-trans retinoic acid [ATRA]-loaded microspheres as therapy for gut inflammation in murine models of inflammatory bowel disease [IBD]. ATRA and TGFβ were separately encapsulated in poly [lactic-co-glycolic] acid or polylactic acid microspheres [respectively]. TGFβ was encapsulated using proprietary phase-inversion nanoencapsulation [PIN] technology. PIN particles provided sustained release of bioactive protein for at least 4 days and were stable for up to 52 weeks when stored at either 4(0)C or -20(0)C. In the SCID mouse CD4 + CD25- T cell transfer model of IBD, oral treatment starting at disease onset prevented weight loss, significantly reduced average disease score [~ 50%], serum amyloid A levels [~ 5-fold], colon weight-to-length ratio [~ 50%], and histological score [~ 5-fold]. Both agents given together outperformed either separately. Highest TGFβ doses and most frequent dose schedule were most effective. Activity was associated with a significant increase [45%] in Foxp3 expression by colonic lamina propria CD4+ CD25+ T-cells. Activity was also demonstrated in dextran sulphate sodium-induced colitis. The data support development of the combination product as a novel, targeted immune based therapy for treatment for IBD.