Abstract
Delivering plasmid DNA (pDNA) to solid tumors remains a significant challenge due to the requirement for multiple transport steps and the need to promote delivery efficiency. Herein, we present a virus-mimicking hybrid lipoplex, composed of an arginine-rich cationic lipid, hyaluronic acid derivatives coated gold nanoparticles, and pDNA. This system induces cytoskeletal rearrangements through "outside-in" mechanical and "inside-out" biochemical signaling, overcoming intra- and intercellular barriers to enhance pDNA delivery. By modulating autophagy, RhoA signaling, and cytoskeletal dynamics, we achieve a 20-fold increase in gene expression with high tissue specificity in solid tumors. Furthermore, the system is applied to co-deliver a p53 plasmid and an MDM2 inhibitor, demonstrating significant synergistic antitumor effects in hepatocellular and lung carcinomas.
© 2025. The Author(s).
MeSH terms
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Animals
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Autophagy* / drug effects
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Carcinoma, Hepatocellular / genetics
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Carcinoma, Hepatocellular / metabolism
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Carcinoma, Hepatocellular / pathology
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Carcinoma, Hepatocellular / therapy
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Cell Line, Tumor
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Cytoskeleton* / metabolism
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DNA / metabolism
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Female
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Genetic Therapy* / methods
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Gold / chemistry
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Humans
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Hyaluronic Acid / chemistry
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Hyaluronic Acid / metabolism
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Lipids / chemistry
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Liver Neoplasms / genetics
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Liver Neoplasms / metabolism
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Liver Neoplasms / therapy
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Lung Neoplasms / genetics
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Lung Neoplasms / metabolism
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Lung Neoplasms / pathology
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Lung Neoplasms / therapy
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Metal Nanoparticles / chemistry
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Mice
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Mice, Nude
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Plasmids / genetics
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Signal Transduction*
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Tumor Suppressor Protein p53 / genetics
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Tumor Suppressor Protein p53 / metabolism
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rhoA GTP-Binding Protein* / genetics
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rhoA GTP-Binding Protein* / metabolism
Substances
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rhoA GTP-Binding Protein
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Gold
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RHOA protein, human
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Hyaluronic Acid
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Tumor Suppressor Protein p53
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Lipids
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DNA