Tumor microenvironment (TME) plays an important role in the tumorigenesis, proliferation, invasion and metastasis. Thereby developing synergistic anticancer strategies with multiple mechanisms are urgent. Copper is widely used in the treatment of tumor chemodynamic therapy (CDT) due to its excellent laser-mediated photo-Fenton-like reaction. Additionally, copper can induce cell death through cuproptosis, which is a new modality different from the known death mechanisms and has great promise in tumor treatment. Herein, we report a natural small molecules carrier-free injectable hydrogel (NCTD Gel) consisted of Cu 2+ -mediated self-assembled glycyrrhizic acid (GA) and norcantharidin (NCTD), which are mainly governed by coordination and hydrogen bonds. Under 808 nm laser irradiation, NCTD Gel can produce reactive oxygen species (ROS), consume glutathione (GSH) and overcome hypoxia in TME, leading to synergistically regulate TME via apoptosis, cuproptosis and anti-inflammation. In addition, NCTD Gel’s CDT display high selectivity and good biocompatibility as it relies on the weak acidity and H 2 O 2 overexpression of TME. Notably, NCTD Gel’s components are originated from clinical agents and its preparation process is easy, green and economical, without any excipients. This study provides a new carrier-free hydrogel synergistic antitumor strategy, which has a good prospect in industrial production and clinical transformation. Graphical abstract Image 1 Highlights • A copper ion-mediated natural small molecules carrier-free injectable hydrogel (NCTD Gel) has been developed. • NCTD Gel with laser-mediated photo-Fenton-like reaction can be used in the treatment of tumor chemodynamic therapy (CDT). • NCTD Gel regulates tumor microenvironment by synergy apoptosis, cuproptosis and anti-inflammation.
【저자키워드】 tumor microenvironment, Cuproptosis, Laser-mediated photo-fenton-like reaction, Natural small molecular ternary carrier-free hydrogel,