Abstract 5748: Inhibition of tumor growth using exosomes loaded with KRAS siRNA and surface-modified with tumor-targeted proapoptotic peptide

Abstract

Abstract Exosomes are extracellular vesicles naturally secreted by cells and serve as carriers of RNAs and proteins for cell-to-cell communications. KRAS is frequently mutated and plays a vital role in many tumors. Receptor expressed in lymphoid tissue (RELT), also known as tumor necrosis factor receptor superfamily 19-like, is upregulated in certain tumors such as lung and pancreatic tumors and is a potential tumor target. To selectively deliver cytotoxic agents to tumor, we loaded mesenchymal stem cell (MSC)-derived exosomes with a siRNA against KRAS and surface-modified them with the RELTpep-KLA peptide comprising a RELT-binding peptide (CRQTKN, named RELTpep) and proapoptotic peptide (KLAKLAKKLAKLAK, named KLA). Exosomes were isolated from cell culture medium using ultracentrifugation and transfected with the KRAS siRNA using a lipid-based reagent and then surfaced-modified with the RELTpep-KLA using a phospholipid-based membrane anchor. Compared with control peptide-KLA, RELTpep-KLA-targeted MSC-exosomes were more efficiently internalized into A549 lung tumor and Panc-1 pancreatic tumor cells expressing RELT on their surface and exhibited cytotoxicity to these tumor cells. RELTpep-KLA-targeted and KRAS siRNA-loaded MSC-exosomes reduced the phosphorylation of Erk and exhibited an enhanced cytotoxicity in A549 and Panc-1 tumor cells. Moreover, when intravenously injected, they inhibited tumor growth in Balb/c nude mice bearing subcutaneous Panc-1 human tumor xenografts more efficiently than those loaded with control siRNA or modified with control peptide-KLA. These results demonstrate that RELTpep-KLA-targeted MSC-exosomes carrying KRAS siRNA hold a potential for exosome-based targeted therapy against cancer. Citation Format: Li Kang, Soyeon Jeon, Sri Murugan Vadevoo, Sang-Hyun Kim, Byungheon Lee. Inhibition of tumor growth using exosomes loaded with KRAS siRNA and surface-modified with tumor-targeted proapoptotic peptide [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5748.