STING agonist-boosted mRNA immunization via intelligent design of nanovaccines for enhancing cancer immunotherapy

Lei Zhou; Wenzhe Yi; Zehong Zhang; Xiaoting Shan; Zitong Zhao; Xiangshi Sun; Jue Wang; Hao Wang; Hualiang Jiang; Mingyue Zheng; Dangge Wang; Yaping Li

doi:10.1093/nsr/nwad214

STING agonist-boosted mRNA immunization via intelligent design of nanovaccines for enhancing cancer immunotherapy

Natl Sci Rev. 2023 Aug 11;10(10):nwad214. doi: 10.1093/nsr/nwad214. eCollection 2023 Oct.

Authors

Lei Zhou^{1

2}, Wenzhe Yi^{1

3}, Zehong Zhang^{4

3}, Xiaoting Shan^{1

3}, Zitong Zhao¹, Xiangshi Sun¹, Jue Wang^{1

3}, Hao Wang², Hualiang Jiang^{4

3}, Mingyue Zheng^{4

3}, Dangge Wang⁵, Yaping Li^{1

3

6}

Affiliations

¹ State Key Laboratory of Drug Research & Center of Pharmaceutics, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
² China State Institute of Pharmaceutical Industry, Shanghai 201203, China.
³ Univerisity of Chinese Academy of Sciences, Beijing 100049, China.
⁴ Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
⁵ Precision Research Center for Refractory Diseases, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 201620, China.
⁶ Shandong Laboratory of Yantai Drug Discovery, Bohai Rim Advanced Research Institute for Drug Discovery, Yantai 264000, China.

Abstract

Messenger RNA (mRNA) vaccine is revolutionizing the methodology of immunization in cancer. However, mRNA immunization is drastically limited by multistage biological barriers including poor lymphatic transport, rapid clearance, catalytic hydrolysis, insufficient cellular entry and endosome entrapment. Herein, we design a mRNA nanovaccine based on intelligent design to overcome these obstacles. Highly efficient nanovaccines are carried out with machine learning techniques from datasets of various nanocarriers, ensuring successful delivery of mRNA antigen and cyclic guanosine monophosphate-adenosine monophosphate (cGAMP) to targets. It activates stimulator of interferon genes (STING), promotes mRNA-encoded antigen presentation and boosts antitumour immunity in vivo, thus inhibiting tumour growth and ensuring long-term survival of tumour-bearing mice. This work provides a feasible and safe strategy to facilitate STING agonist-synergized mRNA immunization, with great translational potential for enhancing cancer immunotherapy.

Keywords: STING; cancer immunotherapy; mRNA; nanoparticles; vaccine.