Abstract

Photodynamic therapy (PDT) is a highly promising cancer treatment strategy that employs photosensitizers (PSs) activated by light exposure to trigger cytotoxic reactions. However, the cellular microenvironment significantly influences the response to PDT, making it imperative to develop a physiologically relevant human model for evaluating the PS. Herein, we develop a gut-on-a-chip microsystem that can precisely simulate the mechanical and structural physiological features of the human intestine, while also spatially resolving and tunably light simulating, enabling the evaluation of PS efficacy. The microdevice generates low shear stress through controlled microfluidic flow, which promotes intestinal epithelial cells to polarize rapidly and spontaneously form folds, thereby recreating the structure of intestinal villi. Notably, compared with conventional 2D culture, the gut-on-a-chip model exhibited significantly reduced cell viability following PDT, indicating the critical influence of physiologically relevant microenvironments on the PS efficacy. Furthermore, this system incorporates representative intestinal microbes, enabling an evaluation of PS efficacy in a microbiota-relevant context. Collectively, this gut-on-a-chip system provides a robust and analytically tractable in vitro platform for PS evaluation in a complex intestinal environment.