Abstract 1317: Lung-specific CRISPR/Cas9 delivery using sulfonium lipid nanoparticles effectively suppresses lung metastases by targeting ATAD3A

Abstract Metastasis is the leading cause of cancer-related morbidity and mortality. The lung is the second most common site of metastasis. It is estimated that 20 to 54% of malignant tumors that develop elsewhere in the body will have pulmonary metastases. However, limiting metastatic tumor growth and progression in the lung remains a significant bottleneck. ATAD3A, a mitochondrial-localized protein, has been shown to play a critical role in maintaining the growth and survival of metastatic tumors in the lung. The current challenge lies in genetically depleting ATAD3A in lung metastatic tumors. Among various mRNA delivery systems, lipid nanoparticles (LNPs) are the most advanced for clinical use. While clinical trials mainly focus on mRNA/LNP therapies for liver diseases, the potential for gene editing therapies extends far beyond this and remains underexplored. In our previous work, we developed lung-specific sulfonium lipid nanoparticles (sLNPs) for selective mRNA delivery to the lung. Building on this, we have now created CRISPR-based ATAD3A-targeting nanodrugs, termed ltLNP3AKO, which encapsulate Cas9 mRNA and anti-ATAD3A sgRNA in the lung-specific sLNPs. In an experimental mouse model of lung metastasis, intravenous administration of ltLNP3AKO efficiently and specifically delivered Cas9 mRNA and anti-ATAD3A sgRNA to the lung, where it successfully depleted the ATAD3A gene. Most notably, ltLNP3AKO induced significant regression of lung metastatic tumors without causing lung or systemic inflammation or toxicity in major organs. These groundbreaking results not only highlight the safety and efficacy of the lung-targeted sLNP platform, but also provide a novel approach to selectively inhibit ATAD3A in lung metastases. Our study further demonstrates the great potential to advance gene editing therapies for patients with lung metastases. Citation Format: Fanghui Chen, David O. Popoola, Fan Yang, Wei Zhen, Yamin Li, Yong Teng. Lung-specific CRISPR/Cas9 delivery using sulfonium lipid nanoparticles effectively suppresses lung metastases by targeting ATAD3A [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 1317.