1. Academic Validation
  2. DP7-C-modified liposomes enhance immune responses and the antitumor effect of a neoantigen-based mRNA vaccine

DP7-C-modified liposomes enhance immune responses and the antitumor effect of a neoantigen-based mRNA vaccine

  • J Control Release. 2020 Dec 10;328:210-221. doi: 10.1016/j.jconrel.2020.08.023.
Rui Zhang 1 Lin Tang 1 Yaomei Tian 1 Xiao Ji 1 Qiuyue Hu 1 Bailing Zhou 1 Zhenyu Ding 2 Heng Xu 3 Li Yang 4
Affiliations

Affiliations

  • 1 State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu 610041, China.
  • 2 Department of Pharmacy and Personalized Drug Therapy Key Laboratory of Sichuan Province, Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital, Chengdu 610072, People's Republic of China.
  • 3 Precision Medicine Center, State Key Laboratory of Biotherapy, and Precision Medicine Key Laboratory of Sichuan Province, West China Hospital, Sichuan University and Collaborative Innovation Center, Chengdu, China.
  • 4 State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu 610041, China. Electronic address: yl_tracy@scu.edu.cn.
Abstract

To date, many clinical trials have been carried out with neoantigen-specific mRNA vaccines, and positive results have been achieved. However, further improvements in the efficiency of the intracellular delivery of mRNA and the production of a stronger immune response are still worth studying. In this study, we used the cholesterol-modified cationic peptide DP7 (VQWRIRVAVIRK), which was developed in our previous study, with a transmembrane structure and immunoadjuvant function to modify DOTAP liposomes to create a common mRNA delivery system. This system was intended to improve the efficiency of the delivery of mRNA encoding individualized neoantigens to dendritic cells (DCs) and enhance the activation of DCs. The system serves dual functions as a carrier and as an immunoadjuvant. As a carrier of mRNA, DP7-C-modified DOTAP liposomes (DOTAP/DP7-C) could transfer mRNA efficiently into different type of DCs in vitro. As an immunoadjuvant, DOTAP/DP7-C liposomes were shown to be more efficacious in stimulating DC maturation, CD103+ DC (contributing to antigen presentation) production and proinflammatory cytokine secretion than DOTAP liposomes both in vitro and in vivo. In animal studies, the subcutaneous administration of DOTAP/DP7-C/LL2 neoantigen-encoding mRNA complexes significantly inhibited the growth of LL2 in situ and the growth of subcutaneous tumors and stimulated the production of antigen-specific lymphocyte reactions, which were superior to the DOTAP/LL2 neoantigen-encoding mRNA complex group. In conclusion, DOTAP/DP7-C liposomes may serve as a potential universal mRNA delivery system, providing a simple method to increase the efficiency of intracellular mRNA delivery and the immunostimulatory activity of DCs.

Keywords

Antitumor effect; DP7-C; Neoantigen; Personalized immunotherapy; mRNA vaccine.

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