Abstract
Nucleic acid aptamers, short single-stranded DNA (ssDNA) or RNA molecules generated via systematic evolution of ligands by exponential enrichment (SELEX), have emerged as promising alternatives to traditional antibodies owing to their exceptional specificity and affinity. These unique properties render them invaluable tools in both scientific research and clinical theranostics. In recent years, aptamer-functionalized nanomaterials have demonstrated substantial potential as tumor-targeted drug delivery systems, offering notable advantages such as reduced systemic toxicity and enhanced therapeutic efficacy. In this study, we developed a novel targeted drug delivery system specifically designed for glypican-3 (GPC3)-positive hepatocellular carcinoma (HCC) by conjugating the GPC3-targeted aptamer AP613-1 to liposomes encapsulating doxorubicin (DOX). To enhance the biostability and binding affinity of the aptamer, we constructed an aptamer-embedded triangular nanostructure (mTriangle-AP613-1) using a DNA origami technique. Characterization results revealed that the mTriangle-AP613-1 nanostructure exhibited a significantly improved dissociation constant (K D) of 15.2 ± 0.21 nM and enhanced biosafety profiles compared to free aptamers. Both in vitro and in vivo evaluations demonstrated that DOX-loaded mTriangle-AP613-1-liposomes achieved superior tumor growth inhibition in GPC3-positive tumor models compared to control groups. These findings highlight the potential of mTriangle-AP613-1-liposomes (DOX) as a highly effective nanomedicine platform for targeted cancer therapy. Notably, our results underscore the translational value of aptamer-functionalized nanostructures in advancing precision oncology through optimized drug delivery systems.