Responsive molecularly imprinted nanozyme with H2O2 self-supply cascade catalytic system for targeted enhancement of chemodynamic therapy

Chemodynamic therapy (CDT) is an emerging treatment strategy that kills tumor cells by generating hydroxyl radicals (·OH) via the activation of Fenton/Fenton-like reactions within the tumor microenvironment (TME). Although CDT overcomes drug resistance issues and has minimal side effects, it still faces multiple challenges including low endogenous hydrogen peroxide (H 2 O 2 ) levels, inadequate catalytic efficiency, and targeting issues. To overcome these limitations, a novel precision-targeted responsive molecularly imprinted nanozyme (GZMIP) was developed. Using zeolitic imidazolate framework-8 (ZIF-8)-coated glucose oxidase (GOx) as a carrier (GZ) and the epitope of lactate transporter (MCT4) as the template, an imprinted layer was prepared on the GZ surface via radical polymerization reactions, followed by elution to obtain GZMIP. GZMIP targeted tumor cells with overexpressed MCT4. Upon entering cells, GZMIP occurred responsive cleavage in the acidic environment and GSH overexpressed TME, releasing GOx and copper(II) acrylate (CuA) monomers from the imprinted layer. GOx catalyzed intracellular glucose (Glu) to generate H 2 O 2 , while GSH reduced CuA to Cu + . The subsequent cascade reaction between Cu + and H 2 O 2 generated highly toxic ·OH, inducing cell death. Both in vitro and in vivo experiments demonstrated that GZMIP effectively inhibited tumor cell proliferation, showed a 75 ± 5 % growth inhibition rate in tumor-bearing mouse models, and exhibited excellent biocompatibility. This study innovatively integrated molecular imprinted polymers with nanozyme technology to establish a Fenton-like cascade catalytic system, simultaneously achieving precise delivery and controlled release of catalytic components. This approach significantly improving tumor targeting and therapeutic efficacy, providing a promising strategy for enhanced CDT.