Department of Chemistry, National University of Singapore, Singapore 117543, Singapore.
State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu 610041, P. R. China.
J Am Chem Soc. 2022 Sep 14;144(36):16366-16377. doi: 10.1021/jacs.2c03266. Epub 2022 Aug 29.
Activation of the stimulator of interferon genes (STING) is essential for blocking viral infections and eliciting antitumor immune responses. Local injection of synthetic STING agonists, such as 2'3'-cGAMP [cGAMP = cyclic 5'-guanosine monophosphate (cGMP)-adenosine monophosphate (AMP)], is a promising approach to enhance antiviral functions and cancer immunotherapy. However, the application of such agonists has been hindered by complicated synthetic procedures, high doses, and unsatisfactory systemic immune responses. Herein, we report the design and synthesis of a series of 2'3'-cGAMP surrogates in nanoparticle formulations formed by reactions of AMP, GMP, and coordinating lanthanides. These nanoparticles can stimulate the type-I interferon (IFN) response in both mouse macrophages and human monocytes. We further demonstrate that the use of europium-based nanoparticles as STING-targeted adjuvants significantly promotes the maturation of mouse bone-marrow-derived dendritic cells and major histocompatibility complex class I antigen presentation. Dynamic molecular docking analysis revealed that these nanoparticles bind with high affinity to mouse STING and human STING. Compared with soluble ovalbumin (OVA), subcutaneously immunized europium-based nanovaccines exhibit significantly increased production of primary and secondary anti-OVA antibodies (∼180-fold) in serum, as well as IL-5 (∼28-fold), IFN-γ (∼27-fold), and IFN-α/β (∼4-fold) in splenocytes ex vivo. Compared with the 2'3'-cGAMP/OVA formulation, subcutaneous administration of nanovaccines significantly inhibits B16F10-OVA tumor growth and prolongs the survival of tumor-bearing mice in both therapeutic and protective models. Given the rich supramolecular chemistry with lanthanides, this work will enable a readily accessible platform for potent humoral and cellular immunity while opening new avenues for cost-effective, highly efficient therapeutic delivery of STING agonists.
干扰素基因刺激物（STING）的激活对于阻断病毒感染和引发抗肿瘤免疫反应至关重要。局部注射合成的 STING 激动剂，如 2'3'-cGAMP[ cGAMP=环 5'-鸟苷酸单磷酸（cGMP）-腺苷酸单磷酸（AMP）]，是增强抗病毒功能和癌症免疫治疗的一种有前途的方法。然而，这些激动剂的应用受到复杂的合成程序、高剂量和不尽如人意的全身免疫反应的限制。在此，我们报告了一系列 2'3'-cGAMP 替代品的设计和合成，这些替代品是由 AMP、GMP 和配位镧系元素反应形成的纳米颗粒制剂。这些纳米颗粒可以刺激小鼠巨噬细胞和人单核细胞中的 I 型干扰素（IFN）反应。我们进一步证明，使用基于铕的纳米颗粒作为 STING 靶向佐剂可以显著促进小鼠骨髓来源树突状细胞的成熟和主要组织相容性复合体 I 抗原呈递。动态分子对接分析表明，这些纳米颗粒与小鼠 STING 和人 STING 具有高亲和力。与可溶性卵清蛋白（OVA）相比，皮下免疫基于铕的纳米疫苗在血清中显著增加了初级和次级抗 OVA 抗体的产生（约 180 倍），以及白细胞介素 5（约 28 倍）、干扰素-γ（约 27 倍）和干扰素-α/β（约 4 倍）在脾细胞中体外。与 2'3'-cGAMP/OVA 制剂相比，纳米疫苗的皮下给药在治疗和保护模型中均显著抑制 B16F10-OVA 肿瘤生长并延长荷瘤小鼠的存活时间。鉴于镧系元素丰富的超分子化学，这项工作将为强大的体液和细胞免疫提供一个易于获得的平台，同时为高效、经济的 STING 激动剂治疗性药物输送开辟新途径。
