Nanoscale CaH2 materials for synergistic hydrogen-immune cancer therapy

The bigger pictureConsidering the functions of hydrogen gas (H2), acidic pH, and calcium ions (Ca2+) in antitumor therapies, herein, we propose the use of newly synthesized calcium hydride (CaH2) nanoparticles as an alternative agent for cancer treatment. After dispersion in polyethylene glycol (PEG) and then injection into the tumor, nano-CaH2 can react with water to generate H2, Ca2+, and hydroxyl ions (OH−), simultaneously achieving hydrogen therapy, intracellular Ca2+ overloading, and acidic TME neutralization. In addition, the local nano-CaH2-induced tumor cell apoptosis and efficient TME modulation can activate the immune system, which, working together with cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4), could elicit robust immune responses to effectively defeat the distant tumors. Lastly, by dispersing nano-CaH2 in lipiodol, we obtain nano-CaH2-lipiodol dispersion for enhanced interventional transarterial embolization (TAE) therapy of rabbit liver cancer.Highlights•Nanoscale CaH2 is synthesized by an exfoliation approach•Nano-CaH2 dispersed in PEG200 was employed as an injectable anticancer agent•Local nano-CaH2 injection could realize TME modulation and immuno-hydrogen therapy•Nano-CaH2-lipiodol dispersion as a novel embolic agent for the combined TAE therapySummaryHerein, we prepared CaH2 nanoparticles through liquid-phase exfoliation and first applied them as an antitumor therapeutic agent. Being dispersed in low-molecular-weight polyethylene glycol (PEG) and injected into the tumor, nano-CaH2 would react with water to generate abundant hydrogen gas (H2), calcium ions (Ca2+), and hydroxyl ions (OH−), enabling hydrogen therapy, tumor calcification, and neutralization of acidic tumor microenvironment (TME), respectively. The injectable nano-CaH2 dispersion could lead to significant tumor growth inhibition. In addition, the local nano-CaH2-induced tumor cell apoptosis and TME modulation would activate the immune system and promote tumor infiltration of immune cells, which, working together with immune checkpoint blockade, could elicit robust immune responses to inhibit abscopal distant tumors without direct nano-CaH2 injection. Furthermore, nano-CaH2 could be dispersed in lipiodol to obtain CaH2-lipiodol dispersion for interventional transarterial embolization (TAE) therapy, and they showed obviously improved TAE therapeutic outcome on orthotopic rabbit liver cancer model compared with lipiodol alone.Graphical abstract