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Theranostics 2024; 14(6):2290-2303. doi:10.7150/thno.93395 This issue Cite

Research Paper

Programming peptide-oligonucleotide nano-assembly for engineering of neoantigen vaccine with potent immunogenicity

Zhichu Xiang^1,2, Jianhua Lu¹, Shangrui Rao¹, Chenxing Fu⁶, Yuying Yao⁶, Yongdong Yi¹, Yang Ming², Weijian Sun^1✉, Weisheng Guo^6✉, Xiaoyuan Chen^2,3,4,5✉

1. Department of Gastrointestinal Surgery, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou 325027, China.
2. Departments of Diagnostic Radiology, Surgery, Chemical and Biomolecular Engineering, and Biomedical Engineering, Yong Loo Lin School of Medicine and College of Design and Engineering, National University of Singapore, Singapore 119074, Singapore.
3. Clinical Imaging Research Centre, Centre for Translational Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117599, Singapore.
4. Nanomedicine Translational Research Program, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597, Singapore.
5. Institute of Molecular and Cell Biology, Agency for Science, Technology, and Research (A*STAR), 61 Biopolis Drive, Proteos, Singapore 138673, Singapore.
6. Department of Minimally Invasive Interventional Radiology, the State Key Laboratory of Respiratory Disease, School of Biomedical Engineering & The Second Affiliated Hospital, Guangzhou Medical University, Guangzhou, 510260, China.

✉ Corresponding authors: fame198288com; chen.shawnedu.sg; guo_wei_shengedu.cn.

Abstract

Background: Neoantigen nanovaccine has been recognized as a promising treatment modality for personalized cancer immunotherapy. However, most current nanovaccines are carrier-dependent and the manufacturing process is complicated, resulting in potential safety concerns and suboptimal codelivery of neoantigens and adjuvants to antigen-presenting cells (APCs).

Methods: Here we report a facile and general methodology for nanoassembly of peptide and oligonucleotide by programming neoantigen peptide with a short cationic module at N-terminus to prepare nanovaccine. The programmed peptide can co-assemble with CpG oligonucleotide (TLR9 agonist) into monodispersed nanostructures without the introduction of artificial carrier.

Results: We demonstrate that the engineered nanovaccine promoted the codelivery of neoantigen peptides and adjuvants to lymph node-residing APCs and instigated potent neoantigen-specific T-cell responses, eliciting neoantigen-specific antitumor immune responses with negligible systemic toxicity. Furthermore, the antitumor T-cell immunity is profoundly potentiated when combined with anti-PD-1 therapy, leading to significant inhibition or even complete regression of established melanoma and MC-38 colon tumors.

Conclusions: Collectively, this work demonstrates the feasibility and effectiveness of personalized cancer nanovaccine preparation with high immunogenicity and good biosafety by programming neoantigen peptide for nanoassembly with oligonucleotides without the aid of artificial carrier.

Keywords: neoantigen, assembly, nanovaccine, peptide programming, immunotherapy

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