Multifunctional nano-bomb based on Fe-COF for targeted tumor dual chemodynamic therapy and bioimaging with enhanced ferroptosis and H2O2 self-supply

Chemodynamic therapy (CDT) is seriously limited by the insufficient amounts of both exogenous catalytic ions and endogenous H 2 O 2 in tumors. Herein, a multifunction nano-bomb integrated with calcium peroxide (CaO 2 ) and β-lapachone as donors of H 2 O 2 and GSH-sensitive Fe-based covalent organic framework (COFs) as provider of catalytic ions was constructed for dual cascade-amplified tumor CDT. This hyaluronic acid (HA)-modified nano-bomb could be specially endocytosed by breast cancer cells through a targeting pathway, degraded and released cargoes in response to the high dose of GSH within the cytoplasm. Furthermore, the released CaO 2 and β-lapachone could significantly self-generated sufficient H 2 O 2 , which could dual-cascade amplify CDT and induce severe oxidative to tumors via cooperating with the delivered iron ions from nano-bombs. Moreover, the unloaded iron and calcium ions could further accelerate tumor damage by overloading Ca 2+ and ferroptosis, as accompanied by good magnetic resonance imaging (MRI). In vitro and in vivo studies collectively reveal that this nano-bomb not only self-initiates double cascade-amplified CDT via self-generation of H 2 O 2 , but also efficiently activates ferroptosis and inducing Ca 2+ overloading, consequently significantly tumor growth suppression. This study offers a novel tumor-initiated nano-bomb system for dual cascade-amplified CDT and bioimaging with activated ferroptosis and self-supplying H 2 O 2 . Keywords: Cascade amplification, tumor starvation, chemodynamic therapy, re-education macrophages, Fe-MOF nanosystem.