The hybrid lipoplex induces cytoskeletal rearrangement via autophagy/RhoA signaling pathway for enhanced anticancer gene therapy

Nat Commun. 2025 Jan 2;16(1):339. doi: 10.1038/s41467-024-55727-4.

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.

MeSH terms

  • Animals
  • Autophagy* / drug effects
  • Carcinoma, Hepatocellular / genetics
  • Carcinoma, Hepatocellular / metabolism
  • Carcinoma, Hepatocellular / pathology
  • Carcinoma, Hepatocellular / therapy
  • Cell Line, Tumor
  • Cytoskeleton* / metabolism
  • DNA / metabolism
  • Female
  • Genetic Therapy* / methods
  • Gold / chemistry
  • Humans
  • Hyaluronic Acid / chemistry
  • Hyaluronic Acid / metabolism
  • Lipids / chemistry
  • Liver Neoplasms / genetics
  • Liver Neoplasms / metabolism
  • Liver Neoplasms / therapy
  • Lung Neoplasms / genetics
  • Lung Neoplasms / metabolism
  • Lung Neoplasms / pathology
  • Lung Neoplasms / therapy
  • Metal Nanoparticles / chemistry
  • Mice
  • Mice, Nude
  • Plasmids / genetics
  • Signal Transduction*
  • Tumor Suppressor Protein p53 / genetics
  • Tumor Suppressor Protein p53 / metabolism
  • rhoA GTP-Binding Protein* / genetics
  • rhoA GTP-Binding Protein* / metabolism

Substances

  • rhoA GTP-Binding Protein
  • Gold
  • RHOA protein, human
  • Hyaluronic Acid
  • Tumor Suppressor Protein p53
  • Lipids
  • DNA