Ho Yuan Soon, Cheng Tzu-Chun, Guo Peixuan
Institute of Biochemistry and Molecular Biology, College of Life Sciences, China Medical University, Taichung, Taiwan.
Division of Pharmaceutics and Pharmacology, College of Pharmacy; Center for RNA Nanotechnology and Nanomedicine; James Comprehensive Cancer Center, College of Medicine, The Ohio State University, Columbus, OH, 43210, USA.
RNA Nanomed. 2024;1(1):16-43. doi: 10.59566/isrnn.2024.0101016.
This review describes a new technology to treat breast-cancer-drug-resistance by targeting the ABC as the multi-homo-subunit ATPase, enlightening by the Christmas-lighting budge with serial circuit and the asymmetrical homo-hexamer of the phi29 DNA packaging motor with sequential revolving mechanism. Chemotherapeutics has been widely used in breast cancer treatments, but drug resistance has raised a serious concern. RNA therapeutics has emerged as the third milestone in pharmaceutical drug development. RNA nanoparticles are dynamic, mild, and deformative, resulting in spontaneous, rapid, and efficient accumulation in tumor vasculature after IV injection. Their negative charge and favorable size bypass the nonspecific targeting of vital organs and normal cells. This motile and deformable nature also led to the fast passing of glomerular filters and their movement into the urine for rapid body clearance for those non-tumor-accumulated nanoparticles, resulting in undetectable toxicity. Extracellular vesicles have shown potential as a delivery system for RNAi and chemotherapeutic drugs , contributing to the efficacy of cancer remission. However, the lack of cell-targeting ligands on extracellular vesicles and the nonspecific entry into healthy cells has led to safety concerns. This review addresses how to apply RNA nanotechnology and RNA-ligand displaying extracellular vesicles for specific delivery to breast cancer. The particular focus is on using and combining the RNA and extracellular vesicle technology to deal with breast cancer drug resistance. The targeting capabilities and drug safety can be improved through extracellular vesicle engineering techniques, such as affixing ligands on the extracellular vesicle surface utilizing arrow-tail RNA nanoparticles, ultimately addressing off-target effects and toxicity. Using RNA ligands for specific targeting and the efficient membrane fusion of extracellular vesicles has enabled the development of ligand-displayed extracellular vesicles capable of delivering both RNAi and chemical drugs to cells with precision, effectively inhibiting tumor growth. The negative charge inherent in the vesicles results in electrostatic repulsion, reducing non-specific binding to healthy cells that contain negatively charged lipid membranes. By leveraging the principles of RNA nanotechnology, the engineering of extracellular vesicles offers a promising avenue for addressing breast cancer drug resistance. This review also discusses applying the series of circuit mechanisms in Christmas-decorating-lighting to develop effective therapeutics to combat breast cancer chemoresistance by targeting the ABC drug transporter and breast cancer surface receptors.
本综述介绍了一种通过靶向ABC（作为多同源亚基ATP酶）来治疗乳腺癌耐药性的新技术，其灵感来自于串联电路的圣诞灯预算以及具有顺序旋转机制的phi29 DNA包装马达的不对称同源六聚体。化疗药物已广泛用于乳腺癌治疗，但耐药性已引起严重关注。RNA疗法已成为药物开发的第三个里程碑。RNA纳米颗粒具有动态性、温和性和可变形性，静脉注射后会在肿瘤血管中自发、快速且高效地积累。它们的负电荷和合适的大小避免了对重要器官和正常细胞的非特异性靶向。这种可移动和可变形的特性还导致非肿瘤积累的纳米颗粒快速通过肾小球滤过器并进入尿液以便快速从体内清除，从而产生不可检测的毒性。细胞外囊泡已显示出作为RNA干扰和化疗药物递送系统的潜力，有助于癌症缓解的疗效。然而，细胞外囊泡上缺乏细胞靶向配体以及非特异性进入健康细胞已引发安全问题。本综述探讨了如何应用RNA纳米技术和展示RNA配体的细胞外囊泡来特异性递送至乳腺癌。特别关注的是使用和结合RNA与细胞外囊泡技术来应对乳腺癌耐药性。通过细胞外囊泡工程技术，如利用箭尾RNA纳米颗粒在细胞外囊泡表面固定配体，可以提高靶向能力和药物安全性，最终解决脱靶效应和毒性问题。使用RNA配体进行特异性靶向以及细胞外囊泡的高效膜融合，使得能够开发出能够将RNA干扰和化学药物精确递送至细胞的展示配体的细胞外囊泡，有效抑制肿瘤生长。囊泡固有的负电荷导致静电排斥，减少了与含有带负电荷脂质膜的健康细胞的非特异性结合。通过利用RNA纳米技术的原理，细胞外囊泡工程为解决乳腺癌耐药性提供了一条有前景的途径。本综述还讨论了应用圣诞装饰灯中的一系列电路机制来开发有效的治疗方法，通过靶向ABC药物转运蛋白和乳腺癌表面受体来对抗乳腺癌化疗耐药性。
