Dual-miRNA Guided in-vivo Imaging and Multimodal Nanomedicine Approaches for Precise Hepatocellular Carcinoma Differentiation and Synergistic Cancer Theranostics using DNA Hairpins and Dual-Ligand functionalized Zirconium-MOF Nanohybrids

Abstract

As one of the most common and heterogeneous liver malignancies, hepatocellular carcinoma (HCC) remains a significant clinical challenge due to the lack of biomarkers for early diagnosis, challenges in accurate subtyping, and limitations of current therapeutic strategies with poor efficacy. Herein, based on DNA hairpin probes and dual-ligand zirconium (Zr)-based metal-organic frameworks (DMOFs), the multifunctional nanohybrids (DMOF@MnCO@CuS@Hairpin probe, DMCH) were developed to overcome these diagnostic and therapeutic obstacles. Two improved DNA molecular beacons and APE1 enzyme within HCC cells were utilized for sensitive miRNAs imaging in vivo with high accuracy to differentiate HCC subtypes precisely. Furthermore, this “all-in-one” theranostic platform not only facilitates the generation of active oxygen species and conversion of near-infrared light into heat, but also releases carbon monoxide to inhibit the expression of HSP70 protein to improve photothermal (PTT) therapy efficiency during laser radiation, which enables PTT, photodynamic (PDT), chemodynamic (CDT), and gas therapy (GAT) for HCC treatment simultaneously. The developed nano-theranostics platform provides a novel way for efficient early screening, diagnosis, and intervention of HCC, and paves the path for future “bench-to-bedside” design of theranostics.