What question did this study set out to answer?

The aim is to create a tumor-selective therapeutic method using siRNA-based nanotherapeutics to target ferroptosis in cholangiocarcinoma.

April 5, 2026

Abstract 5664: Targeting cholangiocarcinoma with ferroptosis-inducing siRNA-based nanotherapeutics.

Key Points

The aim is to create a tumor-selective therapeutic method using siRNA-based nanotherapeutics to target ferroptosis in cholangiocarcinoma.
Developed milk-derived nanovesicles coated with EpCAM aptamer for targeted delivery.
Used siRNA against GPX4 and FSP1 to induce ferroptosis in murine CCA cells.
Conducted in vitro assays to assess lactosome uptake and efficacy.
Performed in vivo studies to evaluate safety, tissue distribution, and efficacy in CCA-bearing mice.
EpCAM-coated lactosomes showed significant uptake by CCA cells.
siGPX4/siFSP1-lactosome treatment induced up to 60% ferroptotic cell death in CCA cells after 72 hours.
In treated mice, significant reductions in Gpx4 and FSP1 mRNA expression by 40-60% were observed.
Ferroptosis markers Ptgs2 and Acsl4 were significantly upregulated (p<0.01).
Tumor burden and CCA markers CK19/7 were reduced in treated mice compared to controls.

Abstract

Abstract Background: Cholangiocarcinoma (CCA) is a highly lethal epithelial cell malignancy of the hepatic biliary tract. Efficacy of current standard-of-care therapy is limited. Ferroptosis, an iron-catalyzed, caspase-independent cell death driven by phospholipid peroxidation, has emerged as a novel therapeutic target. Our goal is to develop a tumor-selective therapeutic approach targeting ferroptosis in CCA using siRNA-based nanotherapeutics. Materials 0.001 vs. siNC). In CCA-bearing mice, intravenous administration of siRNA lactosomes was well-tolerated with no liver or systemic toxicity observed and demonstrated robust tumor distribution compared to non-tumorous tissues. Efficacy studies demonstrated that siGPX4/siFSP1-lactosomes significantly reduced intratumor Gpx4 and FSP1 mRNA expression by 40-60% and induced significant upregulation of ferroptosis markers Ptgs2 and Acsl4 (p0.01 vs. siNC). Ferroptosis in siRNA-lactosome treated tumors was confirmed by immunohistochemistry for phospholipid peroxidation markers oxPAPC and 4-HNE. Additionally, proliferation marker Ki67 was significantly downregulated in siGPX4/siFSP1-lactosome treated tumors (p0.05 vs. siNC), indicating ferroptosis-mediated tumor suppression. Importantly, siGPX4/siFSP1-lactosomes reduced tumor burden and expression of CCA markers CK19/7 in treated mice, as compared to control mice. Conclusions: siRNA-based nanotherapeutics targeting CCA can effectively and safely induce ferroptosis in vitro and in vivo, representing a potential therapeutic strategy for CCA treatment. Citation Format: Peyton Classon, Danielle Marie Carlson, Jayla Millender, Irene Yan, Sumera Ilyas, Rory L. Smoot, TUSHAR PATEL, Gregory J. Gores, Davide Povero. Targeting cholangiocarcinoma with ferroptosis-inducing siRNA-based nanotherapeutics abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 5664.

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