Meng Yingcai, Huang Jiaxin, Ding Jinsong, Zhou Haiyan, Li Yong, Zhou Wenhu
Xiangya School of Pharmaceutical Sciences, Central South University, Changsha 410013, Hunan, China.
Xiangya Hospital, Central South University, Changsha 410008, Hunan, China.
Mater Today Bio. 2024 Mar 11;26:101018. doi: 10.1016/j.mtbio.2024.101018. eCollection 2024 Jun.
The cGAS-STING pathway holds tremendous potential as a regulator of immune responses, offering a means to reshape the tumor microenvironment and enhance tumor immunotherapy. Despite the emergence of STING agonists, their clinical viability is hampered by stability and delivery challenges, as well as variations in STING expression within tumors. In this study, we present Mn-phenolic networks as a novel carrier for ADU-S100, a hydrophilic STING agonist, aimed at bolstering immunotherapy. These nanoparticles, termed TMA NMs, are synthesized through the coordination of tannic acid and manganese ions, with surface modification involving bovine serum albumin to enhance their colloidal stability. TMA NMs exhibit pH/GSH-responsive disintegration properties, enabling precise drug release. This effectively addresses drug stability issues and facilitates efficient intracellular drug delivery. Importantly, TMA NMs synergistically enhance the effects of ADU-S100 through the concurrent release of Mn, which serves as a sensitizer of the STING pathway, resulting in significant STING pathway activation. Upon systemic administration, these nanoparticles efficiently accumulate within tumors. The activation of STING pathways not only induces immunogenic cell death (ICD) in tumor cells but also orchestrates systemic remodeling of the immunosuppressive microenvironment. This includes the promotion of cytokine release, dendritic cell maturation, and T cell infiltration, leading to pronounced suppression of tumor growth. Combining with the excellent biocompatibility and biodegradability, this Mn-based nanocarrier represents a promising strategy for enhancing tumor immunotherapy through the cGAS-STING pathway.
cGAS-STING通路作为免疫反应的调节因子具有巨大潜力，为重塑肿瘤微环境和增强肿瘤免疫治疗提供了一种手段。尽管STING激动剂已经出现，但其临床可行性受到稳定性、递送挑战以及肿瘤内STING表达差异的阻碍。在本研究中，我们提出锰-酚类网络作为亲水性STING激动剂ADU-S100的新型载体，旨在加强免疫治疗。这些纳米颗粒称为TMA纳米颗粒，通过单宁酸和锰离子的配位合成，表面修饰牛血清白蛋白以增强其胶体稳定性。TMA纳米颗粒具有pH/谷胱甘肽响应性崩解特性，能够实现精确的药物释放。这有效地解决了药物稳定性问题，并促进了高效的细胞内药物递送。重要的是，TMA纳米颗粒通过同时释放作为STING通路敏化剂的锰，协同增强ADU-S100的作用，导致显著的STING通路激活。全身给药后，这些纳米颗粒在肿瘤内有效积累。STING通路的激活不仅诱导肿瘤细胞发生免疫原性细胞死亡（ICD），还协调免疫抑制微环境的全身重塑。这包括促进细胞因子释放、树突状细胞成熟和T细胞浸润，从而显著抑制肿瘤生长。结合优异的生物相容性和生物降解性，这种基于锰的纳米载体代表了一种通过cGAS-STING通路增强肿瘤免疫治疗的有前景的策略。
