Abstract 4564: Enhancing circulating tumor DNA recovery and liquid biopsy sensitivity with precision liposomal priming agents

Liquid biopsies offer the potential for early cancer detection as well as a non-invasive, real-time window into the evolving tumor as the cancer progresses (Turabi+, 2024 PMID: 39001494). In this context, circulating tumor DNA (ctDNA) - the fraction of cell-free DNA (cfDNA) shed by tumor cells into the bloodstream, has emerged as a promising candidate. It carries the genetic and epigenetic alterations specific to the originating tumor, making it an essential source of information for cancer diagnosis and monitoring. While in patients with advanced cancer and a higher tumor burden the proportion of ctDNA is >10%, and can even exceed 40% of the total cfDNA, this fraction is less than 1% in early-stage tumors making early detections challenging. We hypothesized that manipulating ctDNA biology could improve its recovery and developed a SPE-liposomal “priming agent" which transiently inhibit macrophage mediated clearance (Martin-Alonso/Tabrizi/Xiong+, 2024 PMID: 38236959). The targeting of SPE liposomes to liver macrophages was predominantly size-dependent, utilizing particles with the average hydrodynamic diameter between 230 and 260 nm. This range was designed to match the size of murine liver capillary fenestrae, such that the nanoparticles would preferentially target liver-resident macrophages over hepatocytes. However, effective macrophage priming still required a significant lipid load to increase cfDNA levels in circulation. To improve on our priming agents, we developed three distinct SPE-modified nanoparticles to target macrophage subpopulations in the liver and tumor. These next-generation priming agents enabled a 60-fold reduction in lipid dose while achieving a more than 1500-fold higher recovery of cfDNA compared to untreated mice. Additionally, we show that these nanoparticles provided a marked increase in the detection of mutant duplexes in a transplantation model of colon cancer lung metastases, Luc-MC26 tumor-bearing mice. In summary, we optimized macrophage-targeted nanoparticle-based strategies that significantly improved the recovery of cfDNA, and that enhanced early tumor detection rate. These technologies have the potential to improve the accuracy and sensitivity of liquid biopsies, as well as to extend our fundamental understanding of the in vivo dynamics of circulating nucleic acid structures. Citation Format: Kasturi Chakraborty, Carmen Martin-Alonso, Daniel Kim, Savan Patel, Sahil Patel, Zhenyi An, Shervin Tabrizi, Claire Sullivan, Lily Gao, J. Christopher Love, Viktor A. Adalsteinsson, Sangeeta N. Bhatia. Enhancing circulating tumor DNA recovery and liquid biopsy sensitivity with precision liposomal priming agents [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 4564.