Enzyme-mediated nanoreactors with cascade metabolic modulation for enhanced chemo-chemodynamic combination therapy

Harnessing the significant buildup of lactic acid (LA) within the tumor microenvironment (TME) for metabolic manipulation presents a promising avenue for cancer treatment. Nevertheless, single-agent therapies often fail to address the complex and varying needs of TME heterogeneity, posing a substantial scientific hurdle in oncology. In this context, we employ asymmetric mesoporous silica nanoparticles (AMS NPs) as delivery vehicles, simultaneously loading them with zinc‑cobalt‑manganese ferrite nanoparticles (ZCMF NPs), lactate oxidase (LOX), and doxorubicin (DOX). We enhance tumor-targeting through the incorporation of the internalizing RGD peptide (iRGD), resulting in the formation of a nanoreactor (AMS@ZCMF-LOX-DOX-iRGD NPs). This innovative nanoreactor combines the advantageous hydrodynamic properties of its asymmetric design with the distinctive physicochemical traits of magnetic nanoparticles, facilitating an enzyme-enhanced combination of chemotherapy and chemodynamic therapy (CDT). In particular, the release of multivalent metal ions from the dissociation of ZCMF NPs triggers Fenton-like reactions, reduces glutathione levels, and catalyzes the conversion of endogenous hydrogen peroxide (H 2 O 2 ) into highly cytotoxic hydroxyl radicals ( OH). The metabolic reprogramming of LA by LOX ensures a continuous supply of H 2 O 2 for catalytic reactions, thereby enhancing CDT. The chemotherapeutic drug DOX works in concert with the surge of reactive oxygen species to deliver a powerful tumor-eradicating effect. Importantly, this system simultaneously regulates tumor LA levels and redox metabolism, achieving a synergistic antitumor effect through combined chemo-chemodynamic strategies. This research offers valuable insights for the formulation of targeted and adjustable combination therapies in cancer treatment.