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Home Articles Vol 30,2026 No.8 Detail

Construction and preliminary evaluation ofN-acetylgalactosamine/cyclic peptide co-modified nucleic acid drugs for hepatocellular carcinoma treatment

Published on Sep. 04, 2026Total Views: 1428 times Total Downloads: 362 times Download Mobile

Author: YANG Xuehua 1, 2 XUE Song 1, 2 LIU Zhengping 1, 2 MAO Kaifan 1 ZHANG Hongqian 1 LI Dawei 1, 2 ZHANG Daizhou 1, 2

Affiliation: 1.Shandong Academy of Pharmaceutical Sciences, Shandong Engineering Research Center of New Sustained and Controlled Release Formulations and Drug Targeted Delivery Systems,Jinan250101,China 2.Shandong Key Laboratory of Targeted Drug Delivery and Advanced Pharmaceutics,Jinan250101,China

Keywords: GalNAc iRGD Nucleic acid drug Hepatocellular carcinoma GalNAc-siPLK1-iRGD

DOI: 10.12173/j.issn.2097-4922.202603058

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Abstract

Objective To construct a small interfering RNA (siRNA) drug co-modified withN-acetylgalactosamine (GalNAc) and internalizing RGD peptide (iRGD peptide) dual ligands, and systematically evaluate its physicochemical properties and in vitro biological functions.

Methods GalNAc-modified siRNA targeting Polo-like kinase 1 (GalNAc-siPLK1) was synthesized via solid-phase synthesis using universal controlled pore glass/GalNAc as the support. Subsequently, the iRGD peptide was site-specifically conjugated through click reaction to obtain the siPLK1 co-modified with GalNAc and iRGD peptide (GalNAc-siPLK1-iRGD). The stability, cellular uptake, cytotoxicity and gene silencing efficiency of GalNAc-siPLK1-iRGD were systematically evaluated using nuclease stability assays, cellular uptake experiments, cytotoxicity experiments, quantitative real-time PCR, and Western blotting analysis.

Results GalNAc-siPLK1-iRGD was successfully synthesized and exhibited enhanced resistance to nuclease degradation, effectively protecting siPLK1 from enzymatic cleavage. Compared to unmodified siPLK1 and GalNAc-siPLK1, GalNAc-siPLK1-iRGD showed significantly increased cellular uptake and markedly enhanced cytotoxicity in HepG2 cells. Moreover, GalNAc-siPLK1-iRGD resulted in more potent downregulation of PLK1 expression at both the mRNA and protein levels.

Conclusion The dual-ligand conjugation strategy incorporating GalNAc and iRGD peptide markedly enhances the stability, cellular uptake, cytotoxicity, and gene silencing efficacy of siPLK1, underscoring its promising potential for targeted therapy in hepatocellular carcinoma.

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