A cascaded enzyme-loaded Fe-hemoporfin framework for synergistic sonodynamic-starvation therapy of tumors.

Enzyme-loaded nanosystems with multimodal therapeutic functions have received increasing attention in the treatment of malignant tumors. Herein, we designed and prepared cascaded dual-enzyme-augmented Fe-hemoporfin framework nanosonosensitizers for synergistic sonodynamic-starvation therapy of tumors. Amorphous Fe-hemoporfin frameworks (FeHF) with an average size of ∼85 nm were synthesized by assembling the clinical drug hemoporfin with Fe ions. Then, FeHF was used to load dual enzymes (glucose oxidase (GOx) and catalase (CAT)) and modified by PEGylated folic acid-conjugated lipids. The dual-enzyme loaded FeHF (FeHF-GOx/CAT) exhibited higher efficiency not only for glucose depletion but also for ultrasound (US)-triggered O generation than that of pure FeHF, resulting from the cascaded catalytic reaction from the dual-enzyme system. As observed by magnetic resonance imaging, the intravenously injected FeHF-GOx/CAT was accumulated within tumors. The FeHF-GOx/CAT + US exhibited the highest inhibition effect compared to the FeHF-CAT + US (only SDT) or FeHF-GOx/CAT (only starvation therapy), due to the synergistic effects of SDT and starvation therapy. Therefore, the cascaded dual-enzyme loading strategy can increase the SDT efficiency of FeHF, which may guide further works in the development of efficient nanosonosensitizers.