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

Author

Listed:
  • Xueyi Hu

    (Sichuan University)

  • Yichun Wang

    (Sichuan University)

  • Ruohan Wang

    (Sichuan University)

  • Yiyao Pu

    (Sichuan University)

  • Rongrong Jin

    (Sichuan University)

  • Yu Nie

    (Sichuan University)

  • Xintao Shuai

    (The Third Affiliated Hospital of Sun Yat-sen University)

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.

Suggested Citation

  • Xueyi Hu & Yichun Wang & Ruohan Wang & Yiyao Pu & Rongrong Jin & Yu Nie & Xintao Shuai, 2025. "The hybrid lipoplex induces cytoskeletal rearrangement via autophagy/RhoA signaling pathway for enhanced anticancer gene therapy," Nature Communications, Nature, vol. 16(1), pages 1-20, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-024-55727-4
    DOI: 10.1038/s41467-024-55727-4
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    References listed on IDEAS

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    1. Wei Wang & Jiang-Jiang Qin & Sukesh Voruganti & Kalkunte S. Srivenugopal & Subhasree Nag & Shivaputra Patil & Horrick Sharma & Ming-Hai Wang & Hui Wang & John K Buolamwini & Ruiwen Zhang, 2014. "The pyrido[b]indole MDM2 inhibitor SP-141 exerts potent therapeutic effects in breast cancer models," Nature Communications, Nature, vol. 5(1), pages 1-12, December.
    2. Lior Rennert & Zichen Ma & Christopher S. McMahan & Delphine Dean, 2022. "Effectiveness and protection duration of Covid-19 vaccines and previous infection against any SARS-CoV-2 infection in young adults," Nature Communications, Nature, vol. 13(1), pages 1-8, December.
    3. Yining Zhu & Ruochen Shen & Ivan Vuong & Rebekah A. Reynolds & Melanie J. Shears & Zhi-Cheng Yao & Yizong Hu & Won June Cho & Jiayuan Kong & Sashank K. Reddy & Sean C. Murphy & Hai-Quan Mao, 2022. "Multi-step screening of DNA/lipid nanoparticles and co-delivery with siRNA to enhance and prolong gene expression," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
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