Abstract
Ulcerative colitis (UC), a chronic inflammatory bowel disease characterized by recurrent colonic mucosal inflammation, substantially impairs patient quality of life. While photodynamic therapy offers promise for UC treatment, conventional photosensitizers face limitations including poor solubility and inadequate targeting. Here, we developed an orally administered multifunctional nanosystem (CBF@LCP) to remodel dysbiotic gut microbiota and enable synergistic phototherapy. The core comprises reactive-oxygen-species-responsive liposomes, encapsulating our previously established iodinated cyanine photosensitizer CyI, and folic acid with bovine serum albumin via amide bonds (CBF@L). This outer layer is coated with a prebiotic chitosan/pectin shell via layer-by-layer assembly. Following oral administration, CBF@LCP withstands the gastrointestinal tract via pH-dependent contraction. Following gastrointestinal-enzyme-mediated decoating, the exposed CBF@L is internalized by folate-receptor-overexpressing M1 macrophages at colitis sites. Under near-infrared irradiation, CyI executes dual photodynamic therapy/photothermal therapy, ablating pro-inflammatory macrophages while exploiting the oxygen-augmented UC microenvironment to enhance reactive oxygen species generation without exogenous oxygen carriers. Concurrently, the prebiotic shell restores microbial eubiosis by suppressing pathogens and promoting beneficial bacteria. In vivo studies in dextran sulfate sodium-induced colitis models demonstrate that CBF@LCP achieves targeted drug release, mitigates inflammation, reprograms macrophage polarization, preserves intestinal barrier integrity, and activates the phosphatidylinositol 3-kinase/AKT signaling pathway. Gut microbiota and transcriptomic analyses confirm restoration of microbial balance and mucosal healing. This work presents a potent targeted strategy for UC management through microbiota remodeling and oxygen-enhanced phototherapy.