Dual‐Targeted Nanovesicles Induced Cancer Stem‐Like Cell Differentiation to Sensitize Hepatocellular Carcinoma Radiotherapy

Abstract Highly plastic cancer stem‐like cells (CSCs) in hepatocellular carcinoma (HCC) drive tumor heterogeneity, contributing to radiotherapy failure. Although inducing CSC differentiation is proven effective in leukemia, this approach is shown limited success in solid tumors due to the complex signaling networks that sustain CSC stemness. In this study, the synergistic effect of Pin1 and Notch1 in HCC is identified, which plays a pivotal role in maintaining the aggressiveness of CSCs and promoting radioresistance. Building on this discovery, biomimetic nanovesicles (CALT‐GM‐NVs) are engineered by infusing tumor cell membranes into liposomes, which exhibit superior binding affinity to CSCs. RNA sequencing reveals that CALT‐GM‐NVs downregulate oncogenic signaling pathways while upregulating those linked to differentiation and apoptosis. In vivo, CALT‐GM‐NVs significantly reduced CSC‐driven radiotolerance and improved radiotherapy efficacy in both cell line‐derived and patient‐derived HCC xenograft models. These findings highlight the potential of simultaneously targeting Pin1 and Notch1 to induce CSC differentiation and provide a promising radiosensitizer for improving HCC radiotherapy outcomes.