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

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A 2D Nanoradiosensitizer Enhances Radiotherapy and Delivers STING Agonists to Potentiate Cancer Immunotherapy
Advanced Materials ( IF 27.4 ) Pub Date : 2022-08-11 , DOI: 10.1002/adma.202110588
Taokun Luo ₁ , Geoffrey T Nash ₁ , Xiaomin Jiang ₁ , Xuanyu Feng ₁ , Jianming Mao ₁ , Jianqiao Liu ₁ , Aditya Juloori ₂ , Alexander T Pearson ₃ , Wenbin Lin _{1,

2}

Affiliation

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.

中文翻译：

2D 纳米放射增敏剂增强放射治疗并提供 STING 激动剂以增强癌症免疫治疗

尽管具有有效的临床前抗肿瘤活性，但干扰素基因刺激剂 (STING) 的激活在临床研究中显示出有限的治疗效果。许多 STING 激动剂，包括 2',3'-环单磷酸鸟苷 - 单磷酸腺苷 (cGAMP)，在维持肿瘤中 STING 激活和实现最佳抗肿瘤功效方面表现出较差的药代动力学特性。需要改进 STING 激动剂的递送及其与其他治疗的有效组合，以增强其治疗效果。本文报道了一种 2D 纳米平台 cGAMP/MOL，通过将 cGAMP 与纳米级金属有机层 (MOL) 结合来同时进行 STING 激活和放射增敏。 MOL不仅表现出强大的放射增敏作用，可增强癌症杀伤和诱导免疫原性细胞死亡，而且还能在肿瘤中保留cGAMP以持续激活STING。与游离 cGAMP 相比，cGAMP/MOL 会引发更强的 STING 激活，并在 X 射线照射下使局部肿瘤消退。与免疫检查点抑制剂的进一步组合通过激活肿瘤微环境以引发全身抗肿瘤反应，从而桥接先天性和适应性免疫系统。

更新日期：2022-08-11

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