A Diselenide-Based Triple-Responsive Nanogel for Tumor Chemo-Photoimmunotherapy

In this study, we successfully developed a diselenide-based, triple-responsive intelligent nanogel, IR780@BEAP, for lung cancer therapy. Exploiting the elevated levels of reactive oxygen species (ROS) and glutathione (GSH) in the tumor microenvironment (TME), a ROS/GSH dual-responsive diselenide cross-linker (DSe5) was synthesized and used to cross-link betulin (BE) with <i>Angelica</i> polysaccharide (AP) while coloading the photosensitizer IR780. The resulting nanogel, IR780@BEAP, exhibited an appropriate particle size (137.7 ± 2.3 nm) and demonstrated excellent colloidal stability. Physicochemical characterization confirmed its dual responsiveness to ROS and GSH, facilitating rapid drug release within the TME. Under near-infrared (NIR) laser irradiation, IR780@BEAP demonstrated good photothermal and photodynamic effects, generating abundant ROS and significantly enhancing antitumor activity. Both in vitro and in vivo experiments confirmed that IR780@BEAP effectively inhibited lung cancer cell proliferation and metastasis, while also inducing apoptosis through combined chemo-phototherapy. Moreover, IR780@BEAP modulated macrophage immune activity by upregulating costimulatory molecules (CD40, CD80, and CD86) and MHC-II expression, thereby activating the immune system and exerting immunotherapeutic effects. Overall, IR780@BEAP, as a smart responsive nanogel, presents a promising approach for combined chemo-photoimmunotherapy in the treatment of lung cancer.