Ultra-efficient radio-immunotherapy for reprogramming the hypoxic and immunosuppressive tumor microenvironment with durable innate immune memory

Jichun Yang; Chong Zhang; Xiaohui Chen; Daijun Zhou; Zixin Sun; Ruyan Niu; Ying Zhu; Hengyi Chen; Liu Wang; Yi Chen; Yuhan Wang; Yunqian Fu; Ningyu Ma; Jianjun Li; Yang Luo

doi:10.1016/j.biomaterials.2023.122303

Ultra-efficient radio-immunotherapy for reprogramming the hypoxic and immunosuppressive tumor microenvironment with durable innate immune memory

Biomaterials. 2023 Nov:302:122303. doi: 10.1016/j.biomaterials.2023.122303. Epub 2023 Sep 5.

Authors

Jichun Yang¹, Chong Zhang², Xiaohui Chen², Daijun Zhou³, Zixin Sun⁴, Ruyan Niu², Ying Zhu⁴, Hengyi Chen⁴, Liu Wang⁴, Yi Chen⁴, Yuhan Wang⁴, Yunqian Fu⁴, Ningyu Ma⁴, Jianjun Li⁵, Yang Luo⁶

Affiliations

¹ Center of Smart Laboratory and Molecular Medicine, School of Medicine, Chongqing University, Chongqing, 400044, PR China. Electronic address: yangjichun@cqu.edu.cn.
² College of Bioengineering, Chongqing University, Chongqing, 400044, PR China.
³ Department of Oncology, First Affiliated Hospital of Army Medical University, Chongqing, 400038, PR China.
⁴ Center of Smart Laboratory and Molecular Medicine, School of Medicine, Chongqing University, Chongqing, 400044, PR China.
⁵ Department of Oncology, First Affiliated Hospital of Army Medical University, Chongqing, 400038, PR China. Electronic address: jianjunli@tmmu.edu.cn.
⁶ Center of Smart Laboratory and Molecular Medicine, School of Medicine, Chongqing University, Chongqing, 400044, PR China; College of Life Science and Laboratory Medicine, Kunming Medical University, Kunming, Yunnan, 650050, PR China. Electronic address: luoy@cqu.edu.cn.

PMID: 37689049
DOI: 10.1016/j.biomaterials.2023.122303

Abstract

Radiosensitization efficacy of conventional tumor radiosensitizers has been frequently limited by insufficient competence for tumor microenvironment (TME) regulation and unfavorable cellular uptake at biological barriers. Here, we reported an ultra-efficient radiotherapy (RT) strategy by synthesizing an extracellular vesicles (EVs)-encapsulated hollow MnO₂ to load metformin (Met@HMnER). It demonstrated significant RT enhancement by morphological control of catalyst and cellular respiratory depression against conventional solid MnO₂. Furthermore, the target-modified EVs clothing retains outstanding metformin loading capacity while endowing enhanced biological barrier penetration. A noticeably durable innate immune activation of NK cells was triggered with this nanoplatform via the cGAS-STING pathway. The enhanced immunocompetence was verified on distal metastasis and in-situ recurrence model in vivo, This work paved a new path for synergistic and robust innate immunity in clinical cancer treatment.

Keywords: Hollow MnO(2); Innate immune effect; Radiotherapy; Tumor microenvironment; Ultra-high efficiency.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Humans
Hypoxia
Immunosuppressive Agents
Immunotherapy
Manganese Compounds
Metformin*
Neoplasms* / therapy
Oxides
Trained Immunity
Tumor Microenvironment

Substances

Manganese Compounds
Oxides
Immunosuppressive Agents
Metformin