STING-Activating Polymers Boost Lymphatic Delivery of mRNA Vaccine to Potentiate Cancer Immunotherapy

Miao Zhang; Yongling Wang; Benhao Li; Bowei Yang; Mengyao Zhao; Bingyu Li; Jianping Liu; Yaxin Hu; Zhaoming Wu; Yenhui Ong; Xiaolin Han; Lingwen Ding; Kongfu Zhu; Jianwei Li; Min Luo; Shengqi Chen; Ling Peng; Longjiang Zhang; Xiaoyuan Chen; Qianqian Ni

doi:10.1002/adma.202412654

STING-Activating Polymers Boost Lymphatic Delivery of mRNA Vaccine to Potentiate Cancer Immunotherapy

Adv Mater. 2024 Dec 23:e2412654. doi: 10.1002/adma.202412654. Online ahead of print.

Authors

Miao Zhang^{1

2}, Yongling Wang^{1

2

3}, Benhao Li^{1

2}, Bowei Yang^{1

2}, Mengyao Zhao^{1

2}, Bingyu Li^{1

2}, Jianping Liu^{1

2}, Yaxin Hu^{1

2}, Zhaoming Wu^{1

2}, Yenhui Ong^{1

2}, Xiaolin Han^{1

2}, Lingwen Ding^{1

2}, Kongfu Zhu⁴, Jianwei Li⁴, Min Luo⁴, Shengqi Chen^{1

2}, Ling Peng⁵, Longjiang Zhang⁶, Xiaoyuan Chen^{1

2

7

8

9

10

9}, Qianqian Ni^{1

2}

Affiliations

¹ Department of Diagnostic Radiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 119074, Singapore.
² Nanomedicine Translational Research Program, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117597, Singapore.
³ Department of Pharmacy, Affiliated Hospital of Zunyi Medical University, Zunyi, 563003, P. R. China.
⁴ Department of Biological Science, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117558, Singapore.
⁵ Centre Interdisciplinaire de Nanoscience de Marseille, Aix-Marseille Universite, CNRS, UMR 7325, ́ "Equipe Labellisee Ligue ́Contre le Cancer", Marseille, 13288, France.
⁶ Department of Medical Imaging, Jinling Hospital, Medical School of Nanjing University, Nanjing, Jiangsu, 210002, China.
⁷ Department of Chemical and Biomolecular Engineering, and Department of Biomedical Engineering, College of Design and Engineering, National University of Singapore, Singapore, 119074, Singapore.
⁸ Department of Pharmacy and Pharmaceutical Sciences, National University of Singapore, Singapore, 117544, Singapore.
⁹ Clinical Imaging Research Centre, Centre for Translational Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117599, Singapore.
¹⁰ Theranostics Center of Excellence (TCE), Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 138667, Singapore.

PMID: 39713955
DOI: 10.1002/adma.202412654

Abstract

The unprecedented success of mRNA vaccines against COVID-19 has inspired scientists to develop mRNA vaccines for cancer immunotherapy. However, using nucleoside modified mRNA as vaccine, though evading innate immune toxicity, diminishes its therapeutic efficacy for cancers. Here, we report a polyvalent stimulator of interferon genes (STING) activating polymer (termed as PD) to bolster the immunogenicity of mRNA vaccine. PD is made of tertiary amine units and conjugated with a biodegradable alkyl chain. Co-formulation of PDs bearing different number of tertiary amines with lipid materials and mRNA resulted in the lipid-like nanoparticles (PD LNPs) which effectively promoted lymphatic delivery and elicited robust immune activation via the STING signaling pathway. Notably, PD with eighteen tertiary amines (PD18) is predominant in balancing immune activity and tolerability. Subcutaneous administration of PD18 LNPs containing ovalbumin (OVA) mRNA enhanced the frequency of antigen specific CD8⁺ T cell with immune memory, leading to potent anticancer efficacy that surpassed 2'3'-cGAMP in both prophylactic and therapeutic cancer models. Additionally, PD18 LNP-based mRNA vaccine showed conferred resistance to cancer challenge for up to 60 days. Overall, this study offers a new perspective of using STING- activating polymer for imparting synergistic activity in mRNA vaccine-based cancer immunotherapy.

Keywords: STING activation; cancer vaccine; lipid nanoparticle; mRNA delivery; polymer.

Abstract

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