Targeted Delivery of Potent Chemical Drugs and RNAi to Drug-Resistant Breast Cancer Using RNA-Nanotechnology and RNA-Ligand Displaying Extracellular vesicles
Authors:   Institute of Biochemistry and Molecular Biology, College of Life Sciences, China Medical University, Taichung, Taiwan, Ho Yuan Soon , Guo Peixuan ,   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, Cheng Tzu-Chun ,   Institute of Biochemistry and Molecular Biology, College of Life Sciences, China Medical University, Taichung, Taiwan;
Published: January 2025

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 in vivo, 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.