Au³⁺-Functionalized Metal–Organic Framework Coordinated Nanotherapeutics for Substrate Self-Supplied Parallel Catalytic and Calcium-Overload-Mediated Therapy of Cancer

The multiple enzymatic properties of the Au³⁺-modified metal-organic framework (Au³⁺-MOFs) have made it a functional catalytic system for antitumor treatment. However, in the face of insufficient catalytic substrates in tumor tissue, it is still impossible to achieve efficient treatment of tumors. Herein, Au³⁺-MOFs loaded with hyaluronic acid (HA)-modified calcium peroxide nanoparticles (CaO₂ NPs) were used to construct a nanozyme (Au³⁺-MOF/CaO₂/HA) for substrate self-supplied and parallel catalytic/calcium-overload-mediated therapy of cancer. Due to the specific targeted ability and retention (EPR) effect of the HA, the built nanozyme can effectively accumulate at the tumor site. Due to the oxidase-like (OXD) activity and peroxidase-like (POD) activity of Au³⁺-MOFs, superoxide radical anion (O₂^•-) and hydroxyl radicals (·OH) were cooperatively formed for parallel catalytic therapy (PCT) of cancer. Subsequently, CaO₂ NPs were decomposed to Ca²⁺, H₂O₂, and O₂ in the weak acidic environment of the tumor microenvironment (TME). Thus, self-supplementation of O₂ as well as H₂O₂ was achieved, alleviating the deficiency of Au³⁺-MOF nanozyme catalytic substrate. In addition, Ca²⁺ can lead to oxidative stress for tumor calcification and calcium-overload-mediated therapy (COMT) to promote tumor necrosis in vivo. An effective paradigm of tumor PCT/COMT therapy with a self-supplying substrate has been successfully established for considerably enhanced therapeutic efficacy.