Manganese molybdate nanodots with dual amplification of STING activation for "cycle" treatment of metalloimmunotherapy

Huali Lei; Quguang Li; Guangqiang Li; Tianyi Wang; Xinjing Lv; Zifan Pei; Xiang Gao; Nailin Yang; Fei Gong; Yuqi Yang; Guanghui Hou; Minjiang Chen; Jiansong Ji; Zhuang Liu; Liang Cheng

doi:10.1016/j.bioactmat.2023.07.026

Manganese molybdate nanodots with dual amplification of STING activation for "cycle" treatment of metalloimmunotherapy

Bioact Mater. 2023 Aug 8:31:53-62. doi: 10.1016/j.bioactmat.2023.07.026. eCollection 2024 Jan.

Authors

Huali Lei¹, Quguang Li¹, Guangqiang Li¹, Tianyi Wang², Xinjing Lv³, Zifan Pei¹, Xiang Gao⁴, Nailin Yang¹, Fei Gong¹, Yuqi Yang¹, Guanghui Hou¹, Minjiang Chen⁵, Jiansong Ji⁵, Zhuang Liu¹, Liang Cheng¹

Affiliations

¹ Institute of Functional Nano & Soft Materials (FUNSOM), Jiangsu Key Laboratory for Carbon-Based Functional Materials and Devices, Soochow University, Suzhou, 215123, China.
² Department of Neurosurgery, The First Affiliated Hospital of Soochow University, Suzhou, 215000, China.
³ Children's Hospital of Soochow University, Pediatric Research Institute of Soochow University, Suzhou, 215123, China.
⁴ Department of Orthopedics, The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu, 215004, China.
⁵ Key Laboratory of Imaging Diagnosis and Minimally Invasive Intervention Research, Fifth Affiliated Hospital of Wenzhou Medical University, Lishui, 323000, Zhejiang, China.

Abstract

Certain types of cationic metal ions, such as Mn²⁺ are able to activate immune functions via the stimulator of interferon genes (STING) pathway, showing potential applications in eliciting antitumor immunity. How anionic ions interact with immune cells remains largely unknown. Herein, selecting from a range of cationic and anionic ions, we were excited to discover that MoO₄^2- could act as a cGAS-STING agonist and further confirmed the capability of Mn²⁺ to activate the cGAS-STING pathway. Inspired by such findings, we synthesized manganese molybdate nanoparticles with polyethylene glycol modification (MMP NDs) for cancer metalloimmunotherapy. Meanwhile, MMP NDs could consume glutathione (GSH) over-expressed in tumors and induce ferroptosis owing to high-valence Mo and Mn to elicit tumor-specific immune responses, which was further amplified by MMP-triggered the cGAS-STING activation. In turn, activated CD8⁺ T cells to secrete high levels of interferon γ (IFN-γ) and reduced GPX4 expression in tumor cells to trigger ferroptosis-specific lipid peroxidation, which constituted a "cycle" of therapy. As a result, the metalloimmunotherapy with systemic administration of MMP NDs offered a remarkable tumor inhibition effect for a variety of tumor models. Our work for the first time discovered the ability of anionic metal ions to activate the immune system and rationally designed bimetallic oxide nanostructures as a multifunctional therapeutic nanoplatform for tumor immunotherapy.

Keywords: DCs maturation; Ferroptosis; Manganese molybdate nanoparticles; Metalloimmunotherapy; cGAS-STING pathway.

Publication types

Review