To improve mRNA vaccine delivery to lymph nodes, Ren, Zhao, and Zhou et al. developed a DTC-modified, PEI-based, transferrin receptor-associating polyplex (TRAP) that enters cells by binding to TfR1, which is highly expressed on monocytes. In mice, s.c. TRAPs induced local inflammation, leading to monocyte recruitment, and effectively bound to and were taken up by TfR1high monocytes, inducing both differentiation into mo-DCs and HEV-mediated trafficking to draining lymph nodes, where mRNA translation and antigen presentation occurred. In tumor models, TRAP-mRNA vaccines elicited strong, antigen-specific, cytotoxic T cell responses, and reduced tumor progression.
Contributed by Lauren Hitchings
Qiongzhe Ren # 1, Xiaofei Zhao # 1, Lili Zhou # 2, Ruonan Ye 1, Liguo Chen 1, Keyun Ren 3, Xijun Piao 3, Yihan Zhou 4, Yiming Qi 5, Kevin C Chan 4, Li Cao 6, Liang Du 7, Peng Gao 7, Bo Ying 7, Chao Deng 1, Fenghua Meng 1, Fangfang Zhou 8, Congcong Xu 9 10 11, Zhiyuan Zhong 12 13 14
To improve mRNA vaccine delivery to lymph nodes, Ren, Zhao, and Zhou et al. developed a DTC-modified, PEI-based, transferrin receptor-associating polyplex (TRAP) that enters cells by binding to TfR1, which is highly expressed on monocytes. In mice, s.c. TRAPs induced local inflammation, leading to monocyte recruitment, and effectively bound to and were taken up by TfR1high monocytes, inducing both differentiation into mo-DCs and HEV-mediated trafficking to draining lymph nodes, where mRNA translation and antigen presentation occurred. In tumor models, TRAP-mRNA vaccines elicited strong, antigen-specific, cytotoxic T cell responses, and reduced tumor progression.
Contributed by Lauren Hitchings
ABSTRACT: Lymph nodes are the primary sites where adaptive immunity is initiated, yet most messenger RNA cancer vaccines reach them inefficiently and instead accumulate in organs such as the liver, limiting therapeutic potency and increasing systemic toxicity. Here we developed a transferrin receptor-associating polyplex formed by electrostatic complexation of mRNA with low-molecular-weight polyethylenimine that had been chemically modified with cyclic disulfide monomers to enhance nucleic acid binding stability, enable thiol-based transferrin receptor engagement and reduce off-target liver uptake. After subcutaneous administration, these polyplexes activated innate immunity, rapidly recruited monocytes with high transferrin receptor expression and bound these cells through cyclic disulfide-mediated interactions. Monocytes then trafficked the vaccine to draining lymph nodes, where mRNA translation and antigen presentation occurred. Delivery of ovalbumin and interleukin 12 mRNA elicited strong antigen-specific cytotoxic T cell responses and inhibited melanoma progression and metastatic disease. Studies using Survivin and human papillomavirus antigens in distinct tumour models demonstrated broad applicability. This monocyte-driven lymph node-targeting strategy enables potent and selective delivery of mRNA cancer vaccines.
Author Info:
1Biomedical Polymers Laboratory, College of Chemistry, Chemical Engineering and Materials Science, Soochow University, Suzhou, P. R. China.
2Institutes of Biology and Medical Scien
ce, Soochow University, Suzhou, P. R. China.
3Catug Biotechnology Co. Ltd, Suzhou, P. R. China.
4Department of Biosciences and Bioinformatics, School of Science, Xi'an Jiaotong-Liverpool University, Suzhou, P. R. China.
5School of Pharmacy, Shanghai Jiao Tong University, Shanghai, P. R. China.
6College of Pharmaceutical Sciences, Soochow University, Suzhou, P. R. China.
7Suzhou Abogen Biosciences Co. Ltd, Suzhou, P. R. China.
8Institutes of Biology and Medical Science, Soochow University, Suzhou, P. R. China. zhoufangfang@suda.edu.cn.
9Biomedical Polymers Laboratory, College of Chemistry, Chemical Engineering and Materials Science, Soochow University, Suzhou, P. R. China. xucc@suda.edu.cn.
10College of Pharmaceutical Sciences, Soochow University, Suzhou, P. R. China. xucc@suda.edu.cn.
11International College of Pharmaceutical Innovation, Soochow University, Suzhou, P. R. China. xucc@suda.edu.cn.
12Biomedical Polymers Laboratory, College of Chemistry, Chemical Engineering and Materials Science, Soochow University, Suzhou, P. R. China. zyzhong@suda.edu.cn.
13College of Pharmaceutical Sciences, Soochow University, Suzhou, P. R. China. zyzhong@suda.edu.cn.
14International College of Pharmaceutical Innovation, Soochow University, Suzhou, P. R. China. zyzhong@suda.edu.cn.
#Contributed equally.
Citation: Nat Biomed Eng 2026 May 5 Epub05/05/2026
