Abstract 6581: Evaluating the impact of the tumor microenvironment on EV-mediated intercellular exchange of nanoparticles

Abstract The limited delivery efficacy of nanoparticles (NPs) continues to impede their clinical translation for cancer therapy. Recent studies have demonstrated that active trans-endothelial pathways dominate NP delivery. While extensive research has focused on endocytosis and subcellular transport, there remains limited understanding of how NPs undergo exocytosis and subsequently re-enter neighboring cells—a process we termed intercellular exchange. Our previous studies established a collagen-based three-dimensional assay designed to specifically quantify the intercellular exchange of NPs and distinguish the contributions of various potential mechanisms. The findings revealed that a significant portion of NPs are transferred within extracellular vesicles (EVs). By modulating EV biogenesis, we successfully altered tumor accumulation and vascular penetration of various NPs in vivo. Here, we further enhance this assay by incorporating critical tumor microenvironment (TME) factors—such as acidity, hypoxia, and the dense extracellular matrix (ECM). This improved model provides a more physiologically relevant platform to evaluate the impact of TME-specific conditions on EV-mediated NP intercellular exchange. Our findings demonstrate that different TME factors exert varying effects on NP transfer efficiency, with ongoing studies evaluating their implications for in vivo delivery. These investigations not only shed light on the mechanisms by which NPs are transported within tumors but also enhance our understanding of the role of EVs in intercellular communication under highly stressed environments. Citation Format: Yiqin Li, Hongbo Pang. Evaluating the impact of the tumor microenvironment on EV-mediated intercellular exchange of nanoparticles [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 6581.