A Tumor Microenvironment-Triggered Calcium Ion and Hydroxyl Radical Amplifier with Near-Infrared Absorption for Photoacoustic Imaging-Guided Calcium Overload-Synergized Multimodal Cancer Therapy

Abstract Calcium overload therapy represents a highly promising therapeutic strategy and has attracted extensive attention in the field of tumor treatment. Nevertheless, the challenge of achieving high-concentration and precise enrichment of calcium ions inside tumors seriously hinders the clinical translation of this therapy. Moreover, monotherapy fails to deliver superior anti-tumor efficacy. To address such issues, a tumor microenvironment (TME)-triggered calcium ion and hydroxyl radical amplifier with near-infrared absorption (CuMPB@CaCO3@HA) is presented to process calcium overload-synergized multimodal combination therapy. It can bind to the CD44 receptor on the surface of cancer cells, thereby accumulating in tumor tissues, where it is decomposed by the TME to release Ca2+ and copper-doped mesoporous Prussian blue (CuMPB). The released Ca2+ triggers intracellular calcium overload. The released CuMPB has a characteristic absorption peak in the range of 650–900 nm, which enables photoacoustic (PA) imaging and photothermal therapy of the tumor. In addition, Cu2+ in CuMPB undergoes a cascade reaction with highly abundant glutathione and H2O2 in the TME, producing hydroxyl radicals (·OH); additionally, the Fe2+ ion in MPB also undergoes a Fenton reaction with H2O2 to generate ·OH, achieving highly efficient chemodynamic therapy (CDT). Moreover, laser irradiation promotes the generation of ·OH, thereby further enhancing CDT. Both in vitro and in vivo experiments verified that CuMPB@CaCO3@HA enables in situ PA diagnosis of tumors to visualize tumor accumulation and optimize the treatment window and enables PA imaging-guided synergistic calcium overload-chemodynamic-photothermal antitumor therapy based on TME characteristics, thus providing a new strategy for the development of tumor-targeted nanotheranostic agents, highlighting the untapped potential of nanoassembly.