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.
Xueyi Hu  #  1 ,  Yichun Wang  #  1 ,  Ruohan Wang  1 ,  Yiyao Pu  1 ,  Rongrong Jin  2 ,  Yu Nie  3 ,  Xintao Shuai  4
Affiliations
  • 1. National Engineering Research Center for Biomaterials, College of Biomedical Engineering, Sichuan University, Chengdu, 610064, P. R. China.
  • 2. National Engineering Research Center for Biomaterials, College of Biomedical Engineering, Sichuan University, Chengdu, 610064, P. R. China. [email protected].
  • 3. National Engineering Research Center for Biomaterials, College of Biomedical Engineering, Sichuan University, Chengdu, 610064, P. R. China. [email protected].
  • 4. Nanomedicine Research Center, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510630, P. R. China.
  • # Contributed equally.
PMID: 39747218 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.

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