H2O2/O2 self-supplementing and GSH-depleting Ca2+ nanogenerator with hyperthermia-triggered, TME-responsive capacities for combination cancer therapy

Abstract The tumor microenvironment (TME) is complex in composition and unique in nature, and is closely related to the growth, invasion and metastasis of tumor cells. Improving and remodeling the TME to return it to a normalized state can fundamentally disrupt the environment and/or nutrient supply on which tumor cells depend. To achieve this goal, based on the unique physicochemical properties and biological effects of CaO2, we designed and constructed a Ca2+ nanogenerator (named as CaO2-Cu/ICG@PCM) that enables H2O2/O2 self-supplementation and GSH depletion. The 808 nm laser induces the heat generation of photosensitizer indocyanine green (ICG) to initiate a series of reactions, followed by the production of copper ions, H2O2, O2 and large amounts of Ca2+, which can eventually lead to the combined treatment of photodynamic therapy (PDT), chemodynamic therapy (CDT) and calcium overload. Additionally, the reaction process is accompanied by the generation of Ca(OH)2, which greatly improves the acidic environment of TME and effectively promotes the oxidation process of GSH by H2O2, achieving the purpose of remodeling TME. It is worth mentioning that a large amount of free Ca2+ accumulating in tumor cells can rapidly initiate the process of calcium overload and calcification, which can not only play a role in tumor suppression, but also assist CT imaging to detect the effect of treatment. Thus, CaO2-Cu/ICG@PCM could be a promising candidate for bioimaging and tumor therapy.