Anti-PD-L1 DNAzyme Loaded Photothermal Mn2+ /Fe3+ Hybrid Metal-Phenolic Networks for Cyclically Amplified Tumor Ferroptosis-Immunotherapy.

Ferroptosis can activate immune response via inducing tumor cells immunogenic cell death (ICD), and antitumor immunity in turn boosts the efficacy of ferroptosis by excreting interferon gamma (IFN-γ), which shows a promising combo for synergistically amplified tumor treatment. However, their combination is strictly limited by the complexity of tumor microenvironment, including poor ferroptosis response and immunosuppressive factors in tumor. Herein, a metal-phenolic networks (MPNs) nanoplatform with all-active components is constructed to favor the ferroptosis-immunotherapy cyclical synergism. The photothermal MPNs are assembled via coordination between tannic acid (TA) and metal-ion complex of Fe3+ /Mn2+ , through which a PD-L1 inhibiting DNAzyme (DZ) is loaded to regulate the immunosuppressive PD-1/PD-L1 pathway. After intracellular delivery, each component of MPNs exerts their respective functions: Fe2+ is in situ generated from Fe3+ by TA reduction to trigger ferroptosis, while DZ is activated by Mn2+ to effectively silence PD-L1. With external laser irradiation, photothermal therapy is initiated to synergize with ferroptosis for enhanced ICD, which induces strong antitumor immunes. Combined with DZ-mediated PD-L1 suppression, a cyclically amplified tumor ferroptosis-immunotherapy is achieved, resulting in obliteration of both primary and distant tumor. This work provides a smart, simple, yet robust nanomedicine-based combination for self-amplified tumor treatment.