ALPPL2‐Binding Peptide Facilitates Targeted mRNA Delivery for Efficient Hepatocellular Carcinoma Gene Therapy

Abstract mRNA‐based gene therapy has emerged as an advanced strategy for hepatocellular carcinoma (HCC) treatment. However, one of its main limitations is lacking delivery precision in vivo. Distinguishing HCC cells from other tissues is crucial for maintaining the high stability, positive therapeutic outcomes, and safety of mRNA therapeutics. Here, a novel HCC specific peptide HCC167 is developed by phage display. It is shown that the HCC167 peptide can specifically recognize variety of HCC substrates including patient samples with high affinity. Modifying nanoparticles with the HCC167 peptide facilitates an effective HCC active targeting ability. When loading with Bims‐encoding mRNA, the systemically administrated DMP‐HCC167/Bims complex efficiently suppresses HCC progression in multiple models including patient‐derived xenografts. Furthermore, the ALPPL2 protein is identified as a specific binding receptor of the HCC167 peptide on the HCC cell membrane, uncovering a new active targeting mechanism based on the HCC167‐ALPPL2 ligand–receptor complex. The binding structure is also investigated by computer‐aided modeling. The study hence exhibits a potent active targeting strategy for mRNA‐based HCC therapy.