Targeted delivery of Fenton reaction packages and drugs for cancer theranostics

Tumor heterogeneity is one of the main reason for the limited therapeutic efficacy of chemotherapeutic drugs. Combinational therapy provides a promising approach to circumvent these limitations. Herein, we report the synthesis of targeted nanoparticles (NPs) encapsulated with multiple therapeutics, which can trigger catalytic cascade reaction in the tumor microenvironments for the combination of chemo-ferroptosis therapy. Therapeutic NPs are prepared by encapsulation of ultra-small gallic acid-iron (GA/Fe) nanocomplexes, glucose oxidase (GOx), and doxorubicin (DOX) into zeolitic imidazole framework-8 (ZIF-8) NPs. Surface functionalization of hyaluronic acid (HA) enables targeted delivery of the encapsulated therapeutics to tumor cells. GOx could consume glucose at tumor sites and generate H2O2, which not only restricts the cellular energy supply but also triggers the Fenton reaction together with the encapsulated iron ions, for promoted lipid peroxidation and therefore ferroptosis therapy. The advantage of the encapsulated GA/Fe nanocomplex lies in its effective delivery of Fe(II) due to the reducing properties of GA for the promoted Fenton reaction compared to Fe(III) and the capacity for magnetic resonance imaging. In addition, the released DOX can also cause tumor cell apoptosis. The targeted NPs provide a promising approach for the delivery of multiple therapeutics in the application of cancer theranostics.