Fibronectin-Coated Metal–Phenolic Networks for Cooperative Tumor Chemo-/Chemodynamic/Immune Therapy via Enhanced Ferroptosis-Mediated Immunogenic Cell Death

Abstract

The development of nanomedicine formulations to overcome the disadvantages of traditional chemotherapeutic drugs and integrate cooperative theranostic modes still remains challenging. Herein, we report the facile construction of a multifunctional theranostic nanoplatform based on doxorubicin (DOX)-loaded tannic acid (TA)-iron (Fe) networks (for short, TAF) coated with fibronectin (FN) for combination tumor chemo-/chemodynamic/immune therapy under the guidance of magnetic resonance (MR) imaging. We show that the DOX-TAF@FN nanocomplexes created through <i>in situ</i> coordination of TA and Fe(III) and physical coating with FN have a mean particle size of 45.0 nm, are stable, and can release both DOX and Fe in a pH-dependent manner. Due to the coexistence of the TAF network and DOX, significant immunogenic cell death can be caused through enhanced ferroptosis of cancer cells via cooperative Fe-based chemodynamic therapy and DOX chemotherapy. Through further treatment with programmed cell death ligand 1 antibody for an immune checkpoint blockade, the tumor treatment efficacy and the associated immune response can be further enhanced. Meanwhile, with FN-mediated targeting, the DOX-TAF@FN platform can specifically target tumor cells with high expression of α_vβ₃ integrin. Finally, the TAF network also enables the DOX-TAF@FN to have an <i>r</i>₁ relaxivity of 6.1 mM^-1 s^-1 for <i>T</i>₁-weighted MR imaging of tumors. The developed DOX-TAF@FN nanocomplexes may represent an updated multifunctional nanosystem with simple compositions for cooperative MR imaging-guided targeted chemo-/chemodynamic/immune therapy of tumors.