A Single-Atom Mn/MoO3- x Nanoagonist for Cascade cGAS/STING Activation in Tumor-Specific Catalytic Metalloimmunotherapy

Xi Hu; Zhiyuan Ma; Bo Zhang; Jie Wang; Yan Zhou; Jun Li; Tianqi Liu; Jingxin Zhang; Bangzhen Hong; Mingjian Zhu; Fangyuan Li; Daishun Ling

doi:10.1002/smll.202407214

A Single-Atom Mn/MoO_3- _x Nanoagonist for Cascade cGAS/STING Activation in Tumor-Specific Catalytic Metalloimmunotherapy

Small. 2024 Nov 5:e2407214. doi: 10.1002/smll.202407214. Online ahead of print.

Authors

Xi Hu^{1

2}, Zhiyuan Ma³, Bo Zhang^{4

5}, Jie Wang^{1

6

7

8}, Yan Zhou³, Jun Li⁴, Tianqi Liu¹, Jingxin Zhang¹, Bangzhen Hong¹, Mingjian Zhu³, Fangyuan Li^{6

7}, Daishun Ling^{4

5}

Affiliations

¹ School of Pharmacy, Anhui Province Key Laboratory of Pharmaceutical Preparation Technology and Application, Anhui University of Chinese Medicine, Hefei, Anhui, 230038, China.
² Institute of Pharmaceutics, Anhui Academy of Chinese Medicine, Hefei, Anhui, 230038, China.
³ Institute of Pharmaceutics, Hangzhou Institute of Innovative Medicine, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China.
⁴ Frontiers Science Center for Transformative Molecules, School of Chemistry and Chemical Engineering, National Center for Translational Medicine, Shanghai Jiao Tong University, Shanghai, 200240, China.
⁵ WLA Laboratories, Shanghai, 201203, China.
⁶ Department of Clinical Laboratory, Songjiang Research Institute, Shanghai Key Laboratory of Emotions and Affective Disorders (LEAD), Songjiang Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 201600, China.
⁷ Key Laboratory of Precision Diagnosis and Treatment for Hepatobiliary and Pancreatic Tumor of Zhejiang Province, Hangzhou, 310009, China.
⁸ School of Chemistry and Chemical Engineering, Hefei University of Technology, Hefei, Anhui, 230009, China.

PMID: 39498728
DOI: 10.1002/smll.202407214

Abstract

The cyclic GMP-AMP synthase (cGAS)/stimulator of interferon genes (STING) pathway plays a crucial role in initiating anti-tumor immunity. Despite the development of various STING agonists, their effectiveness is often limited by suboptimal activation efficiency and poor sustainability. To address this, a Mn/MoO_3- _x nanoagonist featuring Mn single-atom sites is presented, designed for cascade cGAS/STING activation in tumor-specific catalytic metalloimmunotherapy. The single-atom nanoagonist (SANA) is meticulously crafted by doping Mn atoms into defective molybdenum oxide (MoO_3- _x), enabling robust peroxidase-mimicking catalysis and inducing severe double-stranded DNA (dsDNA) damage in tumors. Of note, Mn²⁺ and MoO₄ ^2- can be responsively released from Mn/MoO_3- _x SANA and enhance the sensitivity of cGAS to dsDNA. Importantly, MoO₄ ^2- with a relatively slow-release profile and facile cellular accumulation compensates for Mn²⁺ that has poor cellular accumulation due to continuous efflux, thus continuatively triggering the secretion of type I interferon for beyond 72 h. Remarkably, Mn/MoO_3- _x SANA significantly inhibits tumor growth and metastasis without supplementary STING agonists or external stimulation. This study offers a promising cascade cGAS/STING activation approach to enhance the efficacy and sustainability of catalytic metalloimmunotherapy.

Keywords: cGAS/STING pathway; cascade activation; catalytic metalloimmunotherapy; single‐atom nanoagonist.

Abstract

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