Targeting senescence with radioactive 223Ra/Ba SAzymes enables senolytics-unlocked One-Two punch strategy to boost anti-tumor immunotherapy

Jiajia Zhang; Shenghong Zhang; Chao Cheng; Chunyan Zhu; Taixia Wang; Linglin Tang; Jingjing Lou; Xian Li; Hai Wang; Fan Hu; Ming Sun; Kun Zhang; Fei Yu

doi:10.1016/j.biomaterials.2024.122915

Targeting senescence with radioactive ²²³Ra/Ba SAzymes enables senolytics-unlocked One-Two punch strategy to boost anti-tumor immunotherapy

Biomaterials. 2024 Oct 23:315:122915. doi: 10.1016/j.biomaterials.2024.122915. Online ahead of print.

Authors

Jiajia Zhang¹, Shenghong Zhang², Chao Cheng², Chunyan Zhu³, Taixia Wang³, Linglin Tang⁴, Jingjing Lou⁵, Xian Li⁶, Hai Wang⁷, Fan Hu⁶, Ming Sun⁶, Kun Zhang⁸, Fei Yu⁹

Affiliations

¹ Department of Nuclear Medicine, Shanghai Tenth People's Hospital, Tongji University School of Medicine, No. 301 Yan-chang-zhong Road, Shanghai, 200072, China; Institute of Nuclear Medicine, Tongji University School of Medicine, No. 301 Yan-chang-zhong Road, Shanghai, 200072, China; Central Laboratory and Department of Ultrasound, Sichuan Academy of Medical Sciences, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, No. 32, West Second Section, First Ring Road, Chengdu, 610072, China.
² Department of Nuclear Medicine the First Affiliated Hospital of Navy Medical University (Changhai Hospital), No. 168 Changhai Road, Shanghai, 200433, China.
³ Institute of Nuclear Medicine, Tongji University School of Medicine, No. 301 Yan-chang-zhong Road, Shanghai, 200072, China; Central Laboratory and Department of Ultrasound, Sichuan Academy of Medical Sciences, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, No. 32, West Second Section, First Ring Road, Chengdu, 610072, China.
⁴ Department of Nuclear Medicine, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, No. 160 Pujian Road, Shanghai, 200127, China.
⁵ Department of Nuclear Medicine, Pudong Medical Center, Fudan University, No. 2800 Gongwei Road, Shanghai, 201399, China.
⁶ Department of Nuclear Medicine, Shanghai Tenth People's Hospital, Tongji University School of Medicine, No. 301 Yan-chang-zhong Road, Shanghai, 200072, China; Institute of Nuclear Medicine, Tongji University School of Medicine, No. 301 Yan-chang-zhong Road, Shanghai, 200072, China.
⁷ Central Laboratory and Department of Ultrasound, Sichuan Academy of Medical Sciences, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, No. 32, West Second Section, First Ring Road, Chengdu, 610072, China.
⁸ Central Laboratory and Department of Ultrasound, Sichuan Academy of Medical Sciences, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, No. 32, West Second Section, First Ring Road, Chengdu, 610072, China. Electronic address: [email protected].
⁹ Department of Nuclear Medicine, Shanghai Tenth People's Hospital, Tongji University School of Medicine, No. 301 Yan-chang-zhong Road, Shanghai, 200072, China; Institute of Nuclear Medicine, Tongji University School of Medicine, No. 301 Yan-chang-zhong Road, Shanghai, 200072, China. Electronic address: [email protected].

PMID: 39461062
DOI: 10.1016/j.biomaterials.2024.122915

Abstract

Senescent cells are characterized by a persistent cessation of their cell cycle, rendering them valuable targets for anti-tumor strategies in cancer treatment. Numerous studies have explored induced senescence as a promising approach in tumor therapy. Nevertheless, these treatments often come with drawbacks, including adverse side effects and weaker senescence-inducing effects. To address these challenges, we synthesized ²²³Ra/Ba single-atom nanozyme (SAzyme), wherein Ba SAzyme acts concurrently as a carrier for ²²³RaCl₂, facilitating targeted delivery and minimizing side effects. The ²²³Ra/Ba SAzyme complex enhances various enzyme-mimicking functions, including catalase (CAT) and peroxidase (POD) activities. Importantly, ²²³Ra/Ba SAzyme induces cellular senescence and boost anti-tumor immunity. The persistent presence of a senescence-associated secretory phenotype (SASP) in the tumor microenvironment presents risks of immune suppression and tumor recurrence, which can be effectively mitigated by senolytics. As a result, ²²³Ra/Ba SAzyme were combined with anti-PD-L1 checkpoint blockade to achieve a one-two punch therapy, wherein ²²³Ra/Ba SAzyme exploits senescence followed by anti-PD-L1 therapy to eradicate senescent cells. This one-two punch strategy approach presents a straightforward and potent intervention for both primary tumors and distant tumor.

Keywords: Immunity activation; One‐two punch strategy; Radioactive (223)Ra/Ba single atom nanozymes; Senescence targeting engineering; Senolytics.