Lipid Nanorod-Mediated Codelivery of Inflammasome and STAT3 Inhibitors Attenuates DSS-Induced Colitis

Abstract Ulcerative colitis (UC) is a complex inflammatory bowel disease driven by the coordinated activation of multiple immune pathways, making single-target therapies often insufficient for disease control. Here, we engineered a dual drug-loaded lipid nanorod platform designed to leverage the enhanced cellular internalization of rod-shaped nanoparticles to simultaneously inhibit complementary inflammatory pathways in dextran sulfate sodium (DSS)-induced colitis, including NLRP3 and AIM2 inflammasome signaling and IL-6/STAT3-mediated inflammation, thereby representing a multimechanistic nanotherapeutic strategy. Therapeutic efficacy was evaluated in an acute DSS-induced colitis mouse model and compared with the corresponding free drug combination and the clinical comparator, 5-aminosalicylic acid (5-ASA). Treatment with the dual drug-loaded nanorods significantly mitigated body weight loss (3-fold lower reduction), preserved colon length, and reduced systemic IL-1β (10-fold) relative to the control groups, while demonstrating superior therapeutic efficacy compared with the corresponding free drug combination. Mechanistic studies revealed simultaneous suppression of NLRP3 and AIM2 inflammasome expression, reduced IL-1β production, and marked inhibition of caspase-1 activation, Gasdermin D cleavage, and STAT3 phosphorylation, indicating coordinated regulation of both inflammasome-driven pyroptosis and IL-6-mediated STAT3 signaling cascades. Collectively, this study establishes dual drug-loaded lipid nanorods as a multipathway immunomodulatory platform for treating experimental colitis and supports coordinated nanotherapy as a promising strategy for inflammatory bowel disease.