DNA mechanocapsules for programmable piconewton responsive drug delivery

• Type of Material: Article
• Authors: Arventh Velusamy, Emory University; Radhika Sharma, Emory University; Sk Aysha Rashid, Emory University; Hiroaki Ogasawara, Emory University; Khalid Salaita, Emory University
• Language: English
• Date: 2024
• Publisher: Nature
• Publication Version: Final Published Version
• Copyright Statement: © The Author(s) 2024
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): https://doi.org/10.1038%2Fs41467-023-44061-w
• Title of Journal or Parent Work: Nature Communications
• Volume: 15
• Start Page: 704
• Grant/Funding Information: K.S. acknowledges support from NIH NIAID R01AI172452 and NIGMS R01GM131099 and 1RM1GM145394. We thank Prof. Jonathan Doye, Navoneel Sen, and Hemani Chhabra at the University of Oxford for their discussions on oxDNA simulation and analysis. We thank Prof. Yonggang Ke for his thoughtful discussions on the DMC origami designs. A.V. thanks Joseph Mancuso and Vageesha Herath for their help in characterizing oligonucleotides and their assistance in surface preparation, respectively. Figures in Supplementary Note 1 were Created with BioRender.com.
• Keywords: Drug delivery; Biosensors; DNA nanostructures
• Research Categories: Biology, Genetics

Abstract

The mechanical dysregulation of cells is associated with a number of disease states, that spans from fibrosis to tumorigenesis. Hence, it is highly desirable to develop strategies to deliver drugs based on the “mechanical phenotype” of a cell. To achieve this goal, we report the development of DNA mechanocapsules (DMC) comprised of DNA tetrahedrons that are force responsive. Modeling shows the trajectory of force-induced DMC rupture and predicts how applied force spatial position and orientation tunes the force-response threshold. DMCs functionalized with adhesion ligands mechanically denature in vitro as a result of cell receptor forces. DMCs are designed to encapsulate macromolecular cargos such as dextran and oligonucleotide drugs with minimal cargo leakage and high nuclease resistance. Force-induced release and uptake of DMC cargo is validated using flow cytometry. Finally, we demonstrate force-induced mRNA knockdown of HIF-1α in a manner that is dependent on the magnitude of cellular traction forces. These results show that DMCs can be effectively used to target biophysical phenotypes which may find useful applications in immunology and cancer biology.