Transferrin-modified liposomes enhance chemosensitivity in hepatocellular carcinoma by suppressing RDM1-mediated DNA repair.

RDM1 is linked to poor prognosis in hepatocellular carcinoma (HCC) chemotherapy. We investigated its post-transcriptional regulation and developed a targeted co-delivery strategy to enhance chemosensitivity. Clinical data were analyzed for RDM1 prognostic value. Post-transcriptional regulation by 5-azacytidine (5-Aza) and synergy with doxorubicin (ADM) were assessed via DNA damage repair and apoptosis assays. A transferrin-modified liposome (AA@Tf-Lip) was constructed for co-delivery, and antitumor efficacy evaluated in vitro and in vivo. High RDM1 expression predicted poor HCC survival. 5-Aza downregulated RDM1 by reducing mRNA stability, inhibiting RAD51-mediated homologous recombination repair, and synergistically activating p53/Bax apoptosis with ADM. AA@Tf-Lip enhanced cellular uptake and tumor specificity, achieving higher tumor inhibition and reduced cardiotoxicity versus free drugs. Indirect RDM1 inhibition via post-transcriptional regulation combined with targeted co-delivery effectively enhances HCC chemosensitivity, offering a safe, precise therapeutic strategy.