cGAMP脂质体：一种通用可规模化的STING激动剂佐剂，增强抗感染和抗肿瘤免疫
cGAMP-liposome: A versatile and scalable STING agonist adjuvant for enhanced anti-infective and antitumor immunity
STING通路是疫苗佐剂和肿瘤免疫治疗的热门靶点，但内源性激动剂cGAMP因膜通透性差、易被酶降解和快速经肾清除而难以临床应用。研究者开发了肌肉注射用的cGAMP脂质体，包封率≥90%、粒径70–80纳米，在细胞中激活STING的EC50比游离cGAMP低37倍。在小鼠中，它使抗RBD IgG抗体滴度比铝佐剂提高最多18倍，促进Th1型免疫，并在黑色素瘤模型中抑制肿瘤生长、增加CD8⁺T细胞浸润。注射部位半衰期从0.50小时延长到7.09小时，局部暴露增加43倍，且工艺可放大到1升。
为什么推荐给您：新型可规模化STING佐剂平台，动物数据扎实但尚未进入人体，属值得关注
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摘要Abstract
The Stimulator of Interferon Genes (STING) pathway is a promising target for vaccine adjuvants and cancer immunotherapy, but the clinical application of the endogenous STING agonist 2',3'-cGAMP is hindered by poor membrane permeability, enzymatic degradation, and rapid renal clearance. To address these barriers, we developed a liposome formulation of cGAMP (cGAMP-Lipo) for intramuscular administration. The optimized cGAMP-Lipo exhibited high encapsulation efficiency (≥90 %), a uniform size of 70-80 nm, and enhanced STING activation in THP-1 cells with a 37-fold lower EC50 (45.85 nM) compared to free cGAMP. In vivo, cGAMP-Lipo significantly boosted antigen-specific immune responses, increasing anti-RBD IgG titers by up to 18-fold relative to the aluminum adjuvant and promoting Th1-skewed immunity (IgG2c/IgG1 ratio = 29.6) with a high proportion of effector CD8⁺ T cells. In a B16-OVA melanoma model, cGAMP-Lipo achieved substantial tumor growth inhibition and enhanced CD8⁺ T cell infiltration. Pharmacokinetic studies revealed that cGAMP-Lipo formed a sustained depot at the injection site, extending the local half-life from 0.50 h to 7.09 h and increasing local exposure by 43-fold. Moreover, the manufacturing process was successfully scaled up to 1 L with consistent batch-to-batch reproducibility. Collectively, this work establishes cGAMP-Lipo as a potent, durable, and scalable STING agonist adjuvant platform with strong potential for clinical translation in both infectious disease vaccination and cancer immunotherapy.