Tumor therapy utilizing dual-responsive nanoparticles: A multifaceted approach integrating calcium-overload and PTT/CDT/chemotherapy.

The advancement of rational nano drug delivery systems offers robust tools for achieving synergistic therapeutic outcomes in tumor treatment. In this study, we present the development of pH and near-infrared laser dual-responsive nanoparticles (DOX-CuS@CaCO3@PL-PEG, DCCP NPs) based on calcium carbonate, utilizing a one-pot gas diffusion reaction. These nanoparticles enable combined photothermal therapy (PTT), chemodynamic therapy (CDT), chemotherapy, and Ca2+-overloading synergistic therapy. Doxorubicin (DOX) and copper sulfide (CuS) NPs were co-loaded in CaCO3, followed by PEG surface functionalization. The presence of PEG enhanced the stability of DCCP NPs in aqueous environments. Controlled release of DOX, CuS NPs, and Ca2+ occurs specifically in the acidic tumor microenvironment. Released DOX enhances chemotherapy efficiency, while CuS NPs, upon laser irradiation, induce thermal damage, promoting further drug release and cellular uptake. Additionally, CuS NPs in our system consume excess GSH and generate toxic hydroxyl radicals (·OH) through a Fenton-like reaction, contributing to CDT. These radicals not only directly eliminate tumor cells but also disrupt mitochondrial Ca2+ buffering capacity. Furthermore, Ca2+ released from CaCO3 induces Ca2+-overloading, intensifying mitochondrial disruption and oxidative damage. The synergistic combination of PTT, CDT, chemotherapy, and Ca2+-overloading showcases significant therapeutic potential, indicating broad applications in tumor therapy. This multifaceted approach holds promise for advancing the field of tumor therapeutics.