Department of Chemistry, The University of Chicago, Chicago, IL, 60637, USA.
Department of Radiation and Cellular Oncology and the Ludwig Center for Metastasis Research, The University of Chicago, Chicago, IL, 60637, USA.
Adv Mater. 2022 Sep;34(39):e2110588. doi: 10.1002/adma.202110588. Epub 2022 Aug 26.
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.
尽管具有强大的抗肿瘤前体活性，但干扰素基因刺激物 (STING) 的激活在临床研究中仅显示出适度的治疗效果。许多 STING 激动剂，包括 2',3'-环鸟苷单磷酸-腺苷单磷酸 (cGAMP)，在维持肿瘤中 STING 激活和实现最佳抗肿瘤疗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方法的有效联合，以增强其治疗效果。在此，通过将 cGAMP 与纳米级金属有机层 (MOL) 偶联，报告了一种 2D 纳米平台 cGAMP/MOL，用于同时激活 STING 和放射增敏。MOL 不仅表现出强烈的放射增敏作用，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 在 X 射线照射下引发更强的 STING 激活并使局部肿瘤消退。与免疫检查点抑制剂进一步联合通过激活肿瘤微环境引发全身性抗肿瘤反应，桥接先天和适应性免疫系统。
