School of Chemistry and Chemical Engineering, Frontiers Science Center for Transformative Molecules, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240, China.
Shanghai Frontiers Science Center of TCM Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, 1200 Cailun Road, Shanghai 201203, China.
ACS Nano. 2023 Jun 13;17(11):10090-10103. doi: 10.1021/acsnano.2c12685. Epub 2023 May 30.
Activation of stimulator of interferon genes (STING) can reprogram the immunosuppressive tumor microenvironment (TME) by initiating innate and adaptive immunity. As natural STING agonists, clinical translation of cyclic dinucleotides (CDNs) has been challenged by their short half-life in circulation, poor stability, and low membrane permeability. Herein, we use the natural endogenous small molecules oleic acid and deoxycytidine to construct a ligand for the STING agonist c-di-GMP (CDG), a hydrophobic nucleotide lipid (3',5'-diOA-dC), which can assemble with CDG into stable cyclic dinucleotide nanoparticles (CDG-NPs) through various supramolecular forces driven by molecular recognition. CDG-NPs are homogeneous and stable spherical nanoparticles with an average diameter of 59.0 ± 13.0 nm. Compared with free CDG, CDG-NPs promote the retention and intracellular delivery of CDG in the tumor site, boost STING activation and TME immunogenicity, and potentiate STING-mediated anti-tumor immunity when administered by either intratumoral or systemic routes in melanoma-bearing mice. We propose a flexible supramolecular nanodelivery system for CDG by using endogenous small molecules, which provides a CDN delivery platform for STING-mediated cancer immunotherapy.
干扰素基因刺激物 (STING) 的激活可以通过启动先天和适应性免疫来重新编程免疫抑制性肿瘤微环境 (TME)。作为天然的 STING 激动剂，环二核苷酸 (CDN) 的临床转化受到其在循环中半衰期短、稳定性差和膜通透性低的限制。在此，我们使用天然内源性小分子油酸和脱氧胞苷来构建 STING 激动剂 c-di-GMP (CDG) 的配体，即疏水性核苷酸脂质 (3',5'-diOA-dC)，它可以通过分子识别驱动的各种超分子力与 CDG 组装成稳定的环二核苷酸纳米颗粒 (CDG-NPs)。CDG-NPs 是均一且稳定的球形纳米颗粒，平均直径为 59.0 ± 13.0nm。与游离 CDG 相比，CDG-NPs 促进了 CDG 在肿瘤部位的保留和细胞内递送，增强了 STING 激活和 TME 免疫原性，并在荷黑色素瘤小鼠中通过瘤内或系统途径给药时增强了 STING 介导的抗肿瘤免疫。我们通过使用内源性小分子为 CDG 提出了一种灵活的超分子纳米递药系统，为 STING 介导的癌症免疫治疗提供了一个 CDN 递药平台。
