胰腺癌的肿瘤微环境（TME）具有高度免疫抑制性，其特征是存在大量癌症相关成纤维细胞、骨髓源性抑制细胞和调节性 T 细胞。干扰素基因刺激物（STING）是一种内质网受体，在免疫中发挥着关键作用。 STING 激动剂已证明能够使 TME 发炎、减轻肿瘤负荷并在小鼠模型中赋予抗肿瘤活性。 2'3' 环状鸟苷单磷酸腺苷单磷酸 (2'3'-cGAMP) 是 STING 的高亲和力内源配体。然而，由于膜不通透性和稳定性差，将 cGAMP 递送到胞质内的抗原呈递细胞和肿瘤细胞仍然具有挑战性。在这项研究中，我们将 2'3'-cGAMP 封装在脂质纳米颗粒 (cGAMP-LNP) 中，该脂质纳米颗粒设计用于高效细胞送货。我们通过一系列体外研究评估了纳米粒子的特性，这些研究旨在评估纳米粒子的细胞摄取、胞质释放和最小细胞毒性。此外，我们在同基因小鼠胰腺癌模型中检查了纳米颗粒的抗肿瘤作用。脂质平台显着增加了细胞对 2'3'-cGAMP 的摄取。 cGAMP-LNP 在同基因小鼠胰腺癌模型中表现出良好的抗肿瘤活性。LNP 平台有望在癌症治疗中提供外源 2'3'-cGAMP 或其衍生物。© 2024 Shaji 等人。

The tumor microenvironment (TME) of pancreatic cancer is highly immunosuppressive and characterized by a large number of cancer-associated fibroblasts, myeloid-derived suppressor cells, and regulatory T cells. Stimulator of interferon genes (STING) is an endoplasmic reticulum receptor that plays a critical role in immunity. STING agonists have demonstrated the ability to inflame the TME, reduce tumor burden, and confer anti-tumor activity in mouse models. 2'3' cyclic guanosine monophosphate adenosine monophosphate (2'3'-cGAMP) is a high-affinity endogenous ligand of STING. However, delivering cGAMP to antigen-presenting cells and tumor cells within the cytosol remains challenging due to membrane impermeability and poor stability.In this study, we encapsulated 2'3'-cGAMP in a lipid nanoparticle (cGAMP-LNP) designed for efficient cellular delivery. We assessed the properties of the nanoparticles using a series of in-vitro studies designed to evaluate their cellular uptake, cytosolic release, and minimal cytotoxicity. Furthermore, we examined the nanoparticle's anti-tumor effect in a syngeneic mouse model of pancreatic cancer.The lipid platform significantly increased the cellular uptake of 2'3'-cGAMP. cGAMP-LNP exhibited promising antitumor activity in the syngeneic mouse model of pancreatic cancer.The LNP platform shows promise for delivering exogenous 2'3'-cGAMP or its derivatives in cancer therapy.© 2024 Shaji et al.