Potentiating Oxidative Damage with a Calcium/Copper Nanoplatform for Synergistic Cancer Therapy

Reactive oxygen species (ROS) contribute significantly to tumorigenesis and progression. Inducing cancer cell death and inhibiting tumor growth by regulating the redox level in tumor cells are considered a promising cancer treatment strategy. In this study, we develop a calcium-interference-augmented oxidative damage nanoplatform, denoted as Ce6@MOF199@CaP (CMCa), which is constructed by encapsulating chlorin e6 (Ce6) into a MOF199 framework, followed by coating with a calcium phosphate (CaP) shell. Upon cellular internalization, the CaP shell degrades in the acidic tumor microenvironment, triggering Ca²⁺ overload, which leads to mitochondrial dysfunction and consequently amplifies endogenous ROS generation. Simultaneously, the MOF199 component catalyzes the Fenton-like reaction with hydrogen peroxide (H₂O₂) to produce highly cytotoxic hydroxyl radicals (^•OH) for chemodynamic therapy (CDT), while the photosensitizer Ce6 generates singlet oxygen (¹O₂) upon 660 nm laser irradiation for photodynamic therapy (PDT). This trimodal ROS amplification mechanism, combining calcium overload-potentiated oxidative stress, ^•OH, and ¹O₂, enables a synergistic antitumor effect with significantly enhanced therapeutic efficacy. Our study demonstrates a robust nanotherapeutic strategy for amplifying tumor oxidative damage, providing new perspectives on the development of metal-ion-regulated cancer treatments.