A 2D Nanoradiosensitizer Enhances Radiotherapy and Delivers STING Agonists to Potentiate Cancer Immunotherapy

Abstract

Despite potent preclinical antitumor activity, activation of stimulator of interferon genes (STING) has shown modest therapeutic effects in clinical studies. Many STING agonists, including 2′,3′‐cyclic guanosine monophosphate–adenosine monophosphate (cGAMP), show poor pharmacokinetic properties for sustaining STING activation in tumors and achieving optimal antitumor efficacy. Improved delivery of STING agonists and their effective combination with other treatments are needed to enhance their therapeutic effects. Herein, a 2D nanoplatform, cGAMP/MOL, is reported via conjugating cGAMP to a nanoscale metal–organic layer (MOL) for simultaneous STING activation and radiosensitization. The MOL not only exhibits strong radiosensitization effects for enhanced cancer killing and induction of immunogenic cell death, but also retains cGAMP in tumors for sustained STING activation. Compared to free cGAMP, cGAMP/MOL elicits stronger STING activation and regresses local tumors upon X‐ray irradiation. Further combination with an immune checkpoint inhibitor bridges innate and adaptive immune systems by activating the tumor microenvironment to elicit systemic antitumor responses.

An iodide-containing covalent organic framework for enhanced radiotherapy

“…3 Despite extensive (pre)clinical data that demonstrate the radiosensitizing properties of chemotherapeutic drugs, the intolerable side effects of chemotherapy are clinically limiting its applications. [4][5][6] Nanoparticles containing high-Z elements, such as Au nanoparticles, [7][8][9][10][11] Bi(III) chalcogenides, [12][13][14][15] and metal-organic frameworks (MOFs), [16][17][18][19][20] have recently been used as radiosensitizers. While these inorganic nanomaterials provide large X-ray absorption cross-sections that amplify the radiation energy deposited in tumor tissue and improve radiobiological effects, their biosafety has been questioned.…”

“…Nanoparticles containing high- Z elements, such as Au nanoparticles, 7–11 Bi( iii ) chalcogenides, 12–15 and metal–organic frameworks (MOFs), 16–20 have recently been used as radiosensitizers. While these inorganic nanomaterials provide large X-ray absorption cross-sections that amplify the radiation energy deposited in tumor tissue and improve radiobiological effects, their biosafety has been questioned.…”

Nanoparticle‐Mediated Radiotherapy Remodels the Tumor Microenvironment to Enhance Antitumor Efficacy

“…In recent years, nanoparticles have been developed as potent immune modulators to augment antitumor immune responses of RT by taking advantage of their unique physical and chemical properties. [77][78][79][80][81][82][83] First, nanoparticles can accumulate in lymph nodes, spleen and other lymphatic organs to elicit immune responses due to their tunable structures and sizes. [84,85] Second, nanoparticles can be modified with active targeting molecules for selective delivery of immune-activating drugs to specific immune cells, such as DCs and T cells.…”

“…g) Tumor growth curves after tumor challenge and re-challenge of cured BALB/c mice. a-g) Reproduced with permission [83]. Copyright 2022, The Authors, published by Wiley-VCH.…”

Nanomedicine embraces cancer radio-immunotherapy: mechanism, design, recent advances, and clinical translation

“…Significant response from interferon regulatory factors and excretion of STING-IFN axis-related inflammatory cytokines (IFN-β and IL-6) were observed after treatment with the nano-radiosensitizer compared to the one with cGAMP alone. 126 In another study, an exogenous STING agonist, c-di-AMP, was integrated into a Mn 2+ chelated tannic acid-based nanoplatform to treat large tumors. The level of the second messenger of STING, cGAMP, was significantly increased by 2-fold in the 4T1 tumor tissue in this nano-combinational treatment group in comparison with that in the RT-treated one on day 12 post-treatment.…”