Engineering Radiosensitizer‐Based Metal‐Phenolic Networks Potentiate STING Pathway Activation for Advanced Radiotherapy

Abstract

Beyond technological advances in radiotherapy, including stereotactic body radiation therapy, intensity-modulated radiotherapy, and image-guided radiotherapy, X-ray irradiation in combination with efficient radiosensitizers has also been extensively explored to reduce sideeffects of radiotherapy. [3] Radiosensitizers, chemical drugs or nanoparticles that greatly sensitize tumors to X-ray irradiation, allow improved tumor control while maintaining normal organs tolerance. [4] High-Z metals (e.g., hafnium, gold, and lanthanide elements), as efficient radiosensitizers, may interact with X-ray via several physical processes, releasing Auger electrons, Compton electrons, and photoelectrons. [5] Subsequently, these electrons interact with a water molecule to generate cytotoxic reactive oxygen species (ROS), inducing irreparable DNA lesions. [6] These processes are regarded as radiosensitization. Typically, AGulX, a first-in-class radiosensitizer composed of gadolinium nanoparticles, is currently in the clinical stage. [7] Therefore, developing novel lanthanide-doped radiosensitizers will give more chances to sensitizing radiotherapy for cancer treatment.Moreover, the immunosuppressive tumor microenvironment (TME) severely accelerates tumor radioresistance and results in depressed systemic antitumor immunity. [8] Recently, researchers have demonstrated that ionizing radiation can evoke type I interferon (IFN)-associated adaptive immunity based on stimulator of interferon genes (STING) proteins activation. [9] When undergoing X-ray irradiation, damaged tumor DNA escapes from the nucleus to the cytosol. [10] The as-released cytosolic dsDNA can be sensed by cyclic guanosine monophosphate (GMP)-adenosine monophosphate (AMP) synthase (cGAS), which catalyzes adenylate triphosphate and guanosine triphosphate into 2′,3′-cyclic GMP-AMP and finally activates STING. Such activated STING further binds and activates the tank-binding kinase 1 (TBK1) that phosphorylates the interferon regulatory factor 3 (IRF3), elevating the production of type I IFN. The type I IFN signaling potentiates tumor-specific antigen presentation on dendritic cells (DCs) and cross-prime antitumor T cells for adaptive immunity. Emerging evidence Radiotherapy, a mainstay of first-line cancer treatment, suffers from its high-dose radiation-induced systemic toxicity and radioresistance caused by the immunosuppressive tumor microenvironment. The synergy between radiosensitization and immunomodulation may overcome these obstacles for advanced radiotherapy. Here, the authors propose a radiosensitization cooperated with stimulator of interferon genes (STING) pathway activation strategy by fabricating a novel lanthanide-doped radiosensitizer-based metal-phenolic network, NaGdF 4 :Nd@NaLuF 4 @PEG-polyphenol/Mn (DSPM). The amphiphilic PEG-polyphenol successfully coordinates with NaGdF 4 :Nd@NaLuF 4 (radiosensitizer) and Mn 2+ via robust metal-phenolic coordination. After cell internalization, the pH-responsive disassembly of DSPM triggers the release of their payloads...

Cascade Reaction of “Mn2+‐Catechol” Triggered by H2O2 to Integrate Firm Tumor Vessel Embolization and Hypoxic Response Relief

“…Such slow release of Mn 2+ from the hydrogel might be attributed to the strong coordination interaction between Mn 2+ and active phenolic hydroxyl groups in the PND hydrogel. [28] In addition, catechol groups in the PNDM hydrogel could be oxidized to quinone structures by H 2 O 2 , which was confirmed by the UV absorption curve (Figure S4a, Supporting Information) and the content change of catechol groups before Scheme 1. Schematic illustration of the injectable PND hydrogel coordinating Mn 2+ for enhanced TAE therapy against liver cancer.…”

A protein-based cGAS-STING nanoagonist enhances T cell-mediated anti-tumor immune responses

“…During a typical treatment process, dsDNA derived from tumor cells is captured by DCs and binds with the cytosolic cGAS dimers, thereby activating their enzymatic activity to catalyze the reaction between adenylate triphosphate (ATP) and guanosine triphosphate (GTP) to generate 2′3′ cyclic GMP–AMP (cGAMP) 15 – 17 . cGAMP then binds to the STING dimers to induce STING oligomerization and further activates the TANK-binding kinase 1 (TBK1)-interferon regulatory factor 3 (IRF3) axis to trigger various immunostimulatory signals especially type I interferon (IFN-I) in DCs, which would substantially facilitate the DC-mediated cross-priming of T cells to develop robust antitumor immunity 18 , 19 . Nevertheless, the actual efficacy of several STING agonists in clinical trials was modest at most, revealing multiple key issues for cGAS-STING activation in tumor-encased DCs 20 .…”

Gadolinium-based ultra-small nanoparticles augment radiotherapy-induced T-cell response to synergize with checkpoint blockade immunotherapy

“…17,18 Therefore, a radiosensitizer to ensure the efficiency of RT needs to be urgently found to eliminate the suppression of the immune system produced by high-dose RT. 19…”

“…17,18 Therefore, a radiosensitizer to ensure the efficiency of RT needs to be urgently found to eliminate the suppression of the immune system produced by high-dose RT. 19 Nanoparticles of heavy metals such as gold and hafnium dioxide have been proven to be promising radiosensitizers, which can produce more reactive oxygen species (ROS) to exacerbate DNA breakage. [20][21][22] Activation and guiding of irradiation by X-ray (AGuIX) nanoparticles, a kind of heavymetal nanoparticle, involved polysiloxane and were surrounded by gadolinium chelates.…”