DNA mechanocapsules for programmable piconewton responsive drug delivery

• Published in: Nature communications Vol. 15; no. 1; pp. 704 - 13
• Main Authors: Velusamy, Arventh, Sharma, Radhika, Rashid, Sk Aysha, Ogasawara, Hiroaki, Salaita, Khalid
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 24.01.2024; Nature Publishing Group; Nature Portfolio
• Subjects: 13/106; 14; 14/34; 14/63; 49/31; 49/88; 49/90; 631/61/350/59; 639/638/92/152; 639/925/926/1049; Cancer; Cargo; Cell cycle; Deoxyribonucleic acid; Design; Dextran; Dextrans; DNA; Drug delivery; Drugs; Encapsulation; Fibrosis; Flow cytometry; Humanities and Social Sciences; Hypoxia-inducible factor 1a; Immunology; Ligands; Macromolecules; mRNA; multidisciplinary; Nuclease; Oligonucleotides; Phenotypes; Science; Science (multidisciplinary); Simulation; Tetrahedra; Traction force; Tumorigenesis
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-023-44061-w

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. The mechanical dysregulation of cells is associated with several diseases and strategies to deliver drugs based on the “mechanical phenotype” of a cell are desirable. Here, the authors design and characterize DNA mechanocapsules comprised of DNA tetrahedrons that are force responsive, and showed they can encapsulate macromolecular cargo and release it upon application of force.