Copper-cobalt peroxide nanoparticles: a biomimetic cascade reaction for enhanced Fenton-like therapy at physiologically relevant pH

Traditional Fenton-like reactions, commonly employed in chemodynamic therapy (CDT) for cancer treatment, face limitations due to the mildly acidic tumor microenvironment (TME) and scarce H2O2 availability. Aiming to overcome these hurdles, we report herein the preparation of copper-cobalt peroxide (CCp) nanoparticles, a novel catalyst that enables a pH-activated, self-supplying H2O2-mediated cascade reaction. In the slightly acidic TME (pH 6.5-7.0), CCp nanoparticles degrade, generating H2O2in situ. This intrinsic H2O2 production eliminates the need for external H2O2 sources and enables activation in a significantly higher pH range. Simultaneously, released Cu and Co ions, primarily in lower oxidation states, synergistically drive a catalytic loop for sustained hydroxyl radical ((OH)-O-center dot) production. The non-ferrous bimetallic approach exhibits exquisite pH sensitivity and self-sufficiency, surpassing traditional Fenton reactions. Comparative studies highlight CCp's superior performance against copper-based bimetallic peroxides containing Fe and Ce, confirming the synergistic power of Cu-Co pairing. In vitro experiments demonstrate that the synthesized CCp-NPs exhibit greater toxicity toward breast cancer cells (4T1) than towards non-cancerous cells, showcasing their therapeutic potential. Furthermore, CCp-NPs outperform other nanoparticles in inhibiting cancer cell proliferation, colony formation, and migration. Density Functional Theory (DFT) calculations suggest that Co doping enhances CCp's ability to participate in Fenton reactions. Overall, this work is pioneering in relation to the design of a new class of smart nanoparticles for CDT. The combination of self-generated H2O2, high pH activation, and synergistic metal effects in CCp opens the door for next-generation cancer theranostic nanoparticles with unprecedented efficiency and precision, minimizing side effects.