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

Abstract

Ferroptosis can activate immune response via inducing tumor cells immunogenic cell death (ICD), and antitumor immunity in turn booststhe 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 Fe 3+ /Mn 2+ , 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: Fe 2+ is in situ generated from Fe 3+ by TA reduction to trigger ferroptosis, while DZ is activated by Mn 2+ 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.

Hemin-incorporating DNA nanozyme enabling catalytic oxygenation and GSH depletion for enhanced photodynamic therapy and synergistic tumor ferroptosis

“…Specifically, cytotoxicity of the nanoparticles was passivated upon addition of both ferroptosis inhibitor of ferrostatin-1 (Fer-1) and antidote of glutathione (GSH), but was enhanced by the promoters of glutamate (Glu) and erastin (Era) (Fig. 4E) [30]. All these results demonstrated the critical contribution of hemin-induced ferroptosis for tumor therapy.…”

“…Compared to protein enzymes, DNAzymes are compared favorably for in vivo applications owing to high chemical stability, reversible catalytic activity under harsh conditions (e.g., temperature, organic solvents, wide ranges of pHs), and ease of versatile modifications and labeling with low immunogenicity [26]. Moreover, such DNA-based biomaterials are highly biocompatible and programmable to assemble into DNA nanostructures with controlled size, shape and morphology based on the Watson-Crick base-pairing rules [29], which innovates a new field of DNAzyme-based catalytic therapy [30][31][32][33][34]. Specifically, the catalase-mimic DNAzyme has been reported, which is formed by incorporating hemin into G-rich DNA sequences, and the resulting G-quadruplex (G4)-hemin DNAzyme could effectively decompose H 2 O 2 to generate O 2 .…”

Photothermal Nano-Vaccine Promoting Antigen Presentation and Dendritic Cells Infiltration for Enhanced Immunotherapy of Melanoma via Transdermal Microneedles Delivery

“…In addition to providing a surface for DZ adsorption, the other critical role of the PST core is to act as a photothermal agent. We previously have demonstrated the mild photothermal activity of both PST and TA/Mn 2+ -based MOF [59,61]. Notably, PDM that combined PST and MOF showed a much stronger photothermal efficiency than each respective single structure (Figure S7A).…”

“…As a type of nucleic acid-based drug, a critical challenge of DZ for biomedical application is in vivo degradation. We previously demonstrated that MOF could protect the loaded macromolecules (such as protein and nucleic acids) from enzymatic degradation [59], thus enhancing the biological stability of the payloads. To explore this, we treated the PDM with serum, and the DZ degradation was monitored by gel electrophoresis assay (Figure 2(h)).…”

“…To investigate the photothermal stability of PDM NPs, the PDM NPs solution (2 mL, 400 μg mL -1 ) was irradiated under five laser on/off cycles, and the temperature variation curves were recorded. The photothermal conversion efficiency (η) of PDM NPs was calculated as the previous method [59].…”