Dual-modality immune nano-activator harnessing Mn2⁺ and quercetin to potentiate the cGAS-STING pathway for advanced cancer metalloimmunotherapy

作者：Shanshan Ma, Xuequan Zhang, Xiaoqi Zhu, Kangning Yan, Qin Wang, Lei Lei, J S Li, Jing Guo, Weizhong Tang, Junjie Liu, Jun Cao, Duo Wang, Tao Luo · 发表于：Journal of Nanobiotechnology · 年份：2025 · DOI：10.1186/s12951-025-03336-8 · 被引用次数：21 · 研究领域：interferon and immune responses、Viral Infections and Vectors、Inflammasome and immune disorders

) have emerged as promising activators of the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway. However, their clinical application was hindered by low bioavailability and limited immune activation pathways, which impaired their ability to trigger robust immune responses and achieve significant antitumor effects. To address these challenges, we developed a dual-modality immune nano-activator by coordinating manganese ions with quercetin. This strategy was designed to enhance the cGAS-STING pathway activation and elicit the immunogenic cell death, thereby strengthening the antitumor immune response. The engineered nano-activator demonstrated superior tumor-targeting ability and efficient cellular internalization. Upon exposure to near-infrared irradiation, the system harnessed photothermal effects to induce apoptosis in tumor cells while simultaneously accelerating the release of manganese ions and quercetin. The released manganese ions facilitated the generation of reactive oxygen species, which in conjunction with quercetin-induced apoptosis, amplified photothermal-induced DNA damage. This DNA damage further promoted the release of cytosolic DNA, which in turn activated the cGAS-STING pathway, thereby intensifying immune activation. Notably, the nano-activator also triggered immunogenic cell death, which synergized with the cGAS-STING activation to promote dendritic cell maturation and activate antigen-specific T-cell, significantly enhancing the i...