Abstract 1802: Exosomes-mediated oral gene delivery to treat lung cancer

Abstract Gene therapy is an emerging field in cancer therapeutics that targets specific proteins to control cancer cell proliferation. In recent years, several attempts to treat lung cancer using gene therapy have shown promise, but clinical translatability remains a significant challenge. Factors such as immunogenicity, toxicity, inflammatory responses, and cost-effectiveness hinder the widespread use of gene delivery vectors. Oral delivery of genes could potentially address these challenges; however, achieving therapeutic dosages at the targeted site is difficult due to the degradation of nucleic acids in the gastrointestinal tract before reaching systemic circulation. In the current study, we report a novel exosome-polyethyleneimine (PEI) matrix (EPM) for the oral delivery of nucleic acid therapeutics (siRNA) to treat lung cancer. Exosomes were isolated from bovine colostrum powder by rehydration and differential centrifugation. The tumor-targeting ligand folic acid (FA) was covalently attached to the exosome surface via click chemistry, while PEI was conjugated through ionic interaction to form FA-EPM. The siRNA entrapment efficiency by EPM was found to be more than 90% of the supplied siRNA (up to 20 μg). The transfection efficiency of EPM-siRNA was assessed in vitro via western blot analysis, determining KRAS and NRF2 knockdown in human lung cancer cells (A549). Results demonstrated that EPM-siKRAS and EPM-siNRF2 suppressed KRAS and NRF2 expression by 70-80% in A549 cells in a dose-dependent manner. The therapeutic efficacy of orally administered EPM-siNRF2 and FA-EPM-siKRAS was tested in subcutaneous and orthotopic lung tumor xenografts generated in nude and nod scid mice, respectively. The EPM-siNRF2 formulation inhibited subcutaneous lung tumor growth by 59% compared to control animals (p < 0.01), matching the tumor inhibition by the same formulation administered intravenously. Additionally, orally administered FA-EPM-siKRAS inhibited orthotopic lung tumor growth by 74% (p < 0.01) accompanied with >80% downregulation of the tumor KRAS expression level. This study demonstrated that colostrum exosome-based EPM technology effectively delivers siRNA to tumor sites when administered orally, achieving significant gene knockdown and lung tumor suppression. These findings suggest a simple and effective exosome-based oral gene delivery strategy for cancer therapeutics. Citation Format: Raghuram Kandimalla, Margaret Wallen, Disha N. Moholkar, Jeyaprakash Jeyabalan, Wendy Spencer, Farrukh Aqil, Ramesh C. Gupta. Exosomes-mediated oral gene delivery to treat lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 1802.