ArticleJHEP reports : innovation in hepatology2026
Cell-SELEX identifies a DNA aptamer for highly selective in vivo siRNA delivery in cholangiocarcinoma.
Article in JHEP reports : innovation in hepatology, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
BACKGROUND &
aimsSystematic evolution of ligands by exponential enrichment (SELEX) is a powerful technology for selecting tumor-targeting DNA aptamers from vast pools of trillions of randomly synthesized candidates. We aimed to apply SELEX to identify aptamers capable of selectively delivering therapeutic payloads to murine and human cholangiocarcinoma (CCA). We tested whether this approach enables delivery of small-interfering RNA (siRNA) therapies to knockdown otherwise undruggable oncogene targets.
methodsWe performed 11 rounds of cell-SELEX targeting the human cholangiocarcinoma cell line HuCCT1, with alternating negative selection against normal hepatocytes and cholangiocytes. Over 600 trillion molecules were screened for selective binding, and the specificity of the top aptamer candidate was validated through in vitro binding assays and in vivo biodistribution experiments in mice. Aptamer-guided nanovesicles were loaded with siRNAs targeting undruggable oncogenes and administered to animals bearing orthotopic CCA tumors in a 2-week treatment regimen.
resultsDNA Aptamer 1 selectively bound to CCA cells compared with non-target tissues. Tumor localization of Aptamer 1 was 23-fold higher than liver (p = 0.014), over 6-fold higher than lung (p = 0.004) and heart (p = 0.028), and nearly 3-fold higher than kidneys (p = 0.011). This favorable biodistribution enabled tumor-targeted siRNA delivery via incorporation of Aptamer 1 into the membrane of previously described fusogenic nanovesicles. Tumor protein expression was reduced by 70% or more for three oncogenic targets - YAP (p <0.001), TAZ (p = 0.047), and LCK (p = 0.021) - in orthotopically implanted CCA tumors, with no corresponding knockdown in surrounding liver tissue.
conclusionSELEX identified a novel DNA aptamer enabling tumor-selective delivery of therapeutic payloads against three oncogenes considered to be undruggable. This is a promising advance towards a treatment strategy that has not yet been explored for CCA. IMPACT AND IMPLICATIONS: Platforms for highly tumor-selective delivery of small-interfering RNAs (siRNAs) have the potential to unlock new therapeutic strategies targeting oncogenic proteins previously considered undruggable. SELEX facilitates the identification of DNA aptamers with tumor-specific binding, enabling such approaches. Here, we describe the selection of a novel tumor-targeting aptamer that mediates precise delivery of siRNA-loaded nanovesicles to tumors. These findings represent a significant advance in aptamer-guided, tumor-selective nanovesicle delivery and highlight the potential of this platform for further development toward clinical application.
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