Immunotherapy of Tumor RNA-Loaded Lipid Nanoparticles Against Hepatocellular Carcinoma

Abstract

Yake Zhang,1,2,* Fangyuan Xie,3,* You Yin,4,* Qin Zhang,1,* Hong Jin,5 Yan Wu,6 Liying Pang,7 Jun Li,2 Jie Gao1,2 1Institute of Translational Medicine, Shanghai University, Shanghai, 200444, People’s Republic of China; 2Laboratory of Drug Discovery and Design, School of Pharmacy, Liaocheng University, Liaocheng, 252000, People’s Republic of China; 3Department of Pharmacy, Shanghai Eastern Hepatobiliary Surgery Hospital, Shanghai, 200438, People’s Republic of China; 4Department of Neurology, Changzheng Hospital, Second Military Medical University, Shanghai, 200003, People’s Republic of China; 5Department of Laboratory Medicine, Hongqi Hospital of Mudanjiang Medical College, Mudanjiang, 157011, People’s Republic of China; 6Heilongjiang Key Laboratory of Anti-Fibrosis Biotherapy, Mudanjiang Medical College, Mudanjiang, 157011, People’s Republic of China; 7The First Clinical Medical College of Mudanjiang Medical College, Mudanjiang, 157011, People’s Republic of China*These authors contributed equally to this workCorrespondence: Jie GaoInstitute of Translational Medicine, Shanghai University, Shanghai, 200444, People’s Republic of ChinaTel/Fax + 86-0577-88816381Email [email protected] LiLaboratory of Drug Discovery and Design, School of Pharmacy, Liaocheng University, Liaocheng, 252000, People’s Republic of ChinaTel/Fax + 86-0577-88816381Email [email protected]: Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related deaths worldwide. Most current therapeutic strategies primarily include localized treatment, lacking effective systemic strategies. Meanwhile, recent studies have suggested that RNA vaccines can effectively activate antigen-presenting cells (APCs) and lymphocytes to produce a strong systemic immune response and inhibit tumor growth. However, tumor vaccines loaded with a single tumor antigen may induce immunosuppression and immune evasion, while identifying tumor-specific antigens can require expensive and laborious procedures. Therefore, the use of whole tumor cell antigens are currently considered to be promising, potentially effective, methods. Previously, we developed a targeted liposome-polycation-DNA (LPD) complex nanoparticle that possess a small size, high RNA encapsulation efficiency, and superior serum stability. These particles were found to successfully deliver RNA to tumor sites. In the current study, we encapsulated total tumor-derived RNA in lipid nanoparticles (LNPs) to target dendritic cells (DCs) to incite expeditious and robust anti-tumor immunity.Methods: Total tumor-derived RNA was extracted from liver cancer cells (Hepa1-6 cells). LNPs loaded with tumor RNA were then prepared thin-film hydration method. The ability of RNA LNPs to induce DC maturation, cytotoxicity, and anti-tumor activity, was investigated in vitro and in vivo.Results: The average particle size of LNPs and RNA LNPs was 102.22 ± 4.05 nm and 209.68 ± 6.14 nm, respectively, while the zeta potential was 29.97 ± 0.61 mV and 42.03 ± 0.42 mV, respectively. Both LNPs and RNA LNP vaccines exhibited good distribution and stability. In vitro, RNA LNP vaccines were capable of promoting DC maturation and inducing T lymphocytes to kill Hepa1-6 cells. In vivo, RNA LNP vaccines effectively prevent and inhibit HCC growth.Conclusion: RNA LNPs may serve as an effective antigen specific vaccine to induce anti-tumor immunity for HCC.Keywords: RNA lipid nanoparticles, tumor vaccine, dendritic cells, cancer immunotherapy

Keywords

• rna lipid nanoparticles
• tumor vaccine
• dendritic cells
• cancer immunotherapy