Temperature-activated in situ hydrogel augments tumor treatment

In situ gels with tumor-targeted therapy often struggle with precise spatiotemporal drug release, compromising their efficacy in complex and heterogenous tumors. Here, we present a temperature-activated in situ hydrogel (PTT-Br@mPEG-PLGA and Gem@TCM-TK-PEG in chitosan and PF127 gel, denoted as PP + GC gel. Therein, the photothermal compound PTT-Br is fully named 6-bromo-1-ethyl-2-(2-(6-hydroxy-2,3-dihydro-1H-xanthen-4-yl)vinyl)quinolin-1-ium, while the reactive oxygen species (ROS)-responsive polymer TCM-TK-PEG is fully named tricyano methylene pyridine-thioketal-polyethylene glycol.) with the physiological temperature/photothermal/ROS-responsive drug store and release, thereby maximizing treatment outcomes. After intratumoral injection, PP + GC gel undergoes physiological temperature (37 °C)-responsive sol-gel phase transition, forming stable drug depot for enhanced tumor retention. Upon 635 nm laser irradiation, loaded photothermal agent converts light energy into heat (∼45 °C), triggering photothermal-responsive gel-sol phase transition for actively controlling encapsulated ROS-responsive therapeutic agents release, coupled with photothermal therapy. Subsequently, high levels of ROS in tumor cells disrupt the structure of ROS-responsive therapeutic agents, switching on the chemotherapeutic drug gemcitabine release and further stimulating immune response. Remarkably, laser irradiation of multiple short-duration induces a stronger immune response than that of single long-duration, thus achieving superior treatment outcomes. Benefiting from the smart control of photothermal therapy, chemotherapy, and immunotherapy, active PP + GC gel exhibits a tumor inhibition rate of approximately 82.25 % in melanoma-bearing mouse models, demonstrating significant antitumor efficacy while maintaining excellent biosafety.