Abstract
Ulcerative colitis (UC) is a chronic idiopathic inflammatory bowel disease primarily affecting the colon and rectum, characterized by complex pathogenesis and clinical challenges, such as disease recurrence and potential malignant transformation. The pan-JAK inhibitor tofacitinib (TOF) has emerged as an effective therapeutic option for inducing and maintaining clinical remission in moderate-to-severe UC. Recent advances in nanomedicine have identified milk-derived exosomes (mEXOs) as promising natural drug delivery vehicles due to their favorable physicochemical properties and biocompatibility. Therefore, an oral TOF-loaded mEXOs system (mEXOs@TOF) was successfully developed, which exhibited favorable pharmaceutical characteristics, including stability, uniform size distribution, high drug-loading capacity, and efficient macrophage uptake. The therapeutic efficacy of mEXOs@TOF was mediated through multifaceted mechanisms including suppression of pro-inflammatory cytokines (IL-6, IFN-γ, NO), elevation of anti-inflammatory IL-10 levels, reduction of reactive oxygen species production, and inhibition of JAK-STAT3 signaling pathway activation. Comprehensive in vitro and in vivo assessments of mEXOs@TOF confirmed the enhanced anti-inflammatory treatment on UC, with no detectable adverse effects. Collectively, the mEXOs@TOF nanodelivery system represents a targeted therapeutic strategy for improving UC treatment.