Hu Xueyi, Wang Yichun, Wang Ruohan, Pu Yiyao, Jin Rongrong, Nie Yu, Shuai Xintao
National Engineering Research Center for Biomaterials, College of Biomedical Engineering, Sichuan University, Chengdu, 610064, P. R. China.
Nanomedicine Research Center, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510630, P. R. China.
Nat Commun. 2025 Jan 2;16(1):339. doi: 10.1038/s41467-024-55727-4.
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.
由于需要多个转运步骤以及提高递送效率的需求，将质粒DNA（pDNA）递送至实体瘤仍然是一项重大挑战。在此，我们展示了一种模仿病毒的混合脂质体复合物，它由富含精氨酸的阳离子脂质、包被有透明质酸衍生物的金纳米颗粒和pDNA组成。该系统通过“由外而内”的机械信号和“由内而外”的生化信号诱导细胞骨架重排，克服细胞内和细胞间屏障以增强pDNA递送。通过调节自噬、RhoA信号传导和细胞骨架动力学，我们在实体瘤中实现了基因表达提高20倍且具有高组织特异性。此外，该系统被应用于共同递送p53质粒和MDM2抑制剂，在肝癌和肺癌中显示出显著的协同抗肿瘤作用。
