Kanika_2025_ACS.Appl.Mater.Interfaces__

Developing oral drug delivery systems is promising for ulcerative colitis (UC). However, the key challenges, including formulation degradation under harsh gastric conditions, poor targeting efficiency, and limited colonic residence, lead to poor therapeutic efficacy that still needs to be tackled. Effective treatment requires a safe, efficacious, enzyme- and pH-responsive, biomucoadhesive oral drug delivery system to overcome these challenges. Therefore, we have developed chitosan-armored 1,2-dimyristoyl-sn-glycero-3-phosphoglycerol (DMPG) nanoliposomes amalgamated with synthesized beta-sitosterol-sinapic acid (Be-S) conjugate, further encapsulated with 3,4-methylenedioxy-beta-nitrostyrene (MNS) as NLRP3 inhibitor, termed C@MN@DMBe-S, to overcome the limitation of free MNS and sinapic acid. Formulated by the thin-film hydration method and processed through extrusion, these unilamellar liposomes demonstrated structural stability and mucoadhesive properties due to chitosan coating. This configuration protected the nanoliposomes from the gastric acidic environment and allowed retention in the inflamed colon for 48 h. The enzyme-responsive C@MN@DMBe-S nanoliposome releases sinapic acid at the inflamed colonic site via esterase activity, providing sustained and controlled release of MNS. This synergistic action delivers antioxidant and anti-inflammatory effects while influencing the gut microbiota composition by releasing short-chain fatty acids. Moreover, therapeutic investigations revealed that C@MN@DMBe-S exhibited superior efficacy compared with free MNS when administered orally. The formulation effectively downregulated NF-kappaB, NLRP3, Caspase-1, and IL-1beta expression while upregulating MUC5AC expression, indicating enhanced anti-inflammatory and protective effects and thereby promoting mucosal healing. In addition, C@MN@DMBe-S was found to regulate immune cell expression and effectively downregulate neutrophil infiltration. This armor- and enzyme-responsive strategy elucidates the impact of oral nanomedicines on mitigating UC and is demonstrated as an effective treatment.