Magnetic Targeting, Tumor Microenvironment-Responsive Intelligent Nanocatalysts for Enhanced Tumor Ablation

TLDR

Therapeutic nanosystems triggered by the tumor microenvironment offer high selectivity and safety by converting non‑toxic prodrugs into toxic agents in situ. We constructed magnetic, tumor‑responsive nanocatalysts that enable oxidation therapy of cancer through site‑specific reactions. The nanocatalysts consist of an Fe₅C₂‑GOD core coated with MnO₂ that releases GOD and generates O₂ in acidic tumors, producing H₂O₂ that reacts with Fe₅C₂ to generate hydroxyl radicals while Mn²⁺ provides MRI contrast. The nanocatalysts remained inactive in normal cells, released Mn²⁺ for MRI monitoring, and produced tumor‑specific hydroxyl radicals that enhanced anticancer efficacy with minimal systemic toxicity in mice.

Abstract

Therapeutic nanosystems which can be triggered by the distinctive tumor microenvironment possess great selectivity and safety to treat cancers via in situ transformation of nontoxic prodrugs into toxic therapeutic agents. Here, we constructed intelligent, magnetic targeting, and tumor microenvironment-responsive nanocatalysts that can acquire oxidation therapy of cancer via specific reaction at tumor site. The magnetic nanoparticle core of iron carbide-glucose oxidase (Fe5C2-GOD) achieved by physical absorption has a high enzyme payload, and the manganese dioxide (MnO2) nanoshell as an intelligent "gatekeeper" shields GOD from premature leaking until reaching tumor tissue. Fe5C2-GOD@MnO2 nanocatalysts maintained inactive in normal cells upon systemic administration. On the contrary, after endocytosis by tumor cells, tumor acidic microenvironment induced decomposition of MnO2 nanoshell into Mn2+ and O2, meanwhile releasing GOD. Mn2+ could serve as a magnetic resonance imaging (MRI) contrast agent for real-time monitoring treatment process. Then the generated O2 and released GOD in nanocatalysts could effectively exhaust glucose in tumor cells, simultaneously generating plenty of H2O2 which may accelerate the subsequent Fenton reaction catalyzed by the Fe5C2 magnetic core in mildly acidic tumor microenvironments. Finally, we demonstrated the tumor site-specific production of highly toxic hydroxyl radicals for enhanced anticancer therapeutic efficacy while minimizing systemic toxicity in mice.