A ROS storm generating nanocomposite for enhanced chemodynamic therapy through HO self-supply, GSH depletion and calcium overload.

Catalytic generation of toxic hydroxyl radicals (˙OH) from hydrogen peroxide (HO) is an effective strategy for tumor treatment in chemodynamic therapy (CDT). However, the intrinsic features of the microenvironment in solid tumors, characterized by limited HO and overexpressed glutathione (GSH), severely impede the accumulation of intracellular ˙OH, posing significant challenges. To circumvent these critical issues, in this work, a CaO-based multifunctional nanocomposite with a surface coating of Cu and L-buthionine sulfoximine (BSO) (named CaO@Cu-BSO) is designed for enhanced CDT. Taking advantage of the weakly acidic environment of the tumor, the nanocomposite gradually disintegrates, and the exposed CaO nanoparticles subsequently decompose to produce HO, alleviating the insufficient supply of endogenous HO in the tumor microenvironment (TME). Furthermore, Cu detached from the surface of CaO is reduced by HO and GSH to Cu and ROS. Then, Cu catalyzes HO to generate highly cytotoxic ˙OH and Cu, forming a cyclic catalysis effect for effective CDT. Meanwhile, GSH is depleted by Cu ions to eliminate possible ˙OH scavenging. In addition, the decomposition of CaO by TME releases a large amount of free Ca, resulting in the accumulation and overload of Ca and mitochondrial damage in tumor cells, further improving CDT efficacy and accelerating tumor apoptosis. Besides, BSO, a molecular inhibitor, decreases GSH production by blocking γ-glutamyl cysteine synthetase. Together, this strategy allows for enhanced CDT efficiency a ROS storm generation strategy in tumor therapy. The experimental results confirm and demonstrate the satisfactory tumor inhibition effect both and .