Dual-targeting celecoxib nanoparticles protect intestinal epithelium and regulate macrophage polarization for ulcerative colitis treatment

Ulcerative colitis (UC) is a chronic recurrent disease of the gastrointestinal tract. Though the exact etiology is still unknown, inflamed enterocytes, activated macrophages, and the crosstalk between them have been widely believed to play vital roles in the UC progression. Therefore, simultaneously modulating both injured intestinal epithelial cells and activated immune cells could effectively normalize the intestinal microenvironment by regulating cell-specific activities and breaking the vicious loop between them. Herein, we designed a PepT1 and CD44 dual-targeted celecoxib nanoparticle (Cel@HVGB) that could selectively deliver celecoxib to both the inflamed enterocytes and the activated M1 macrophages for UC treatment. Cel@HVGB exhibited excellent cell-specific targeting ability to both inflamed epitheliums and M1 macrophages. In vitro studies showed that Cel@HVGB could exert an enhanced anti-inflammatory effect and improve the colonic inflammatory microenvironment via directly modulating Nrf2/HO-1 and NF-κB pathways in epithelial cells and promoting M1 to M2 macrophage polarization. In a DSS-induced mice model, Cel@HVGB significantly attenuated bodyweight loss, reduced colon length shortening, lowered the disease activity index score and alleviated colon histological damage. In addition, Cel@HVGB could also regulate the intestinal flora in UC mice toward a healthier state with improved species uniformity and abundance as well as restored species diversity. Notably, both in vivo and in vitro data proved that Cel@HVGB had more robust therapeutic activity than both Cel solution and single targeted nanoparticle. This study provides a potential strategy for UC drug delivery and effective treatment.