A ROS storm generating nanocomposite for enhanced chemodynamic therapy through H2O2 self-supply, GSH depletion and calcium overload

Abstract

Catalytic generation of toxic hydroxyl radicals (˙OH) from hydrogen peroxide (H₂O₂) is an effective strategy for tumor treatment in chemodynamic therapy (CDT). However, the intrinsic features of the microenvironment in solid tumors, characterized by limited H₂O₂ and overexpressed glutathione (GSH), severely impede the accumulation of intracellular ˙OH, posing significant challenges. To circumvent these critical issues, in this work, a CaO₂-based multifunctional nanocomposite with a surface coating of Cu²⁺ and L-buthionine sulfoximine (BSO) (named CaO₂@Cu–BSO) is designed for enhanced CDT. Taking advantage of the weakly acidic environment of the tumor, the nanocomposite gradually disintegrates, and the exposed CaO₂ nanoparticles subsequently decompose to produce H₂O₂, alleviating the insufficient supply of endogenous H₂O₂ in the tumor microenvironment (TME). Furthermore, Cu²⁺ detached from the surface of CaO₂ is reduced by H₂O₂ and GSH to Cu⁺ and ROS. Then, Cu⁺ catalyzes H₂O₂ to generate highly cytotoxic ˙OH and Cu²⁺, forming a cyclic catalysis effect for effective CDT. Meanwhile, GSH is depleted by Cu²⁺ ions to eliminate possible ˙OH scavenging. In addition, the decomposition of CaO₂ by TME releases a large amount of free Ca²⁺, resulting in the accumulation and overload of Ca²⁺ 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 via a ROS storm generation strategy in tumor therapy. The experimental results confirm and demonstrate the satisfactory tumor inhibition effect both in vitro and in vivo.