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New Project Explores Cytosolic Access and Instability of DNA Nanoparticles

Divita Mathur, Research Assistant Professor, is studying cytosolic access and instability of DNA nanoparticles.

A number of candidate therapies such as CRISPR-Cas9 and gene silencing require the efficient delivery of functional nucleic acids to the cell cytosol and nucleus. Unfortunately, such therapies currently lack proper delivery mechanisms, precluding their widespread applicability.

Self-assembled deoxyribonucleic acid (DNA) have shown potential as minimally cytotoxic therapeutic carriers and other in vitro and in vivo models. While evidence suggests that DNA nanoparticle-based drug carriers can be taken up by mammalian cells via endocytosis, it is unknown how these DNA nanoparticles can overcome the fate of endocytosis-triggered degradation to reach the cytosol, and once there, controllably maintain stability. With the enabling science explaining their behavior and mechanisms of controlling their stability in the cell cytosol, it will be possible to make bold advances in engineering therapeutic delivery systems.

To that end, the proposed work has two overarching scientific payoffs.

The first is that it will induce endosomal escape and enhance cytosolic accessibility of DNA nanoparticles and integration of calcium in their assembly process.

The second is that it will identify the rate of breakdown and mechanisms of stabilization of DNA nanoparticles in different types of cell cytosols. Innovative technologies will be the foci of Mathur's training program and will be implemented to achieve the project goals, namely multi-step Förster resonance energy transfer spectroscopy for high-resolution tracking of DNA nanoparticles inside the cell and in vitro cell microinjections enabling study of these nanoparticles directly in the cytosolic environment.

Regarding the project's importance, Mathur said: "Synthetic DNA-based nanoparticles possess the potential to develop advanced delivery tools for targeted therapies, but their behavior in the cytosolic environment remains poorly understood. Herein, we seek to address critical issues about the accessibility and breakdown of these nanoparticles within the mammalian cell cytosol and identify mechanisms of stabilization. Outcomes of the proposed project will enable the realization of more-biocompatible delivery systems."

Mathur received $92,880 from the U.S. Department of Health and Human Services for this project. Funding began in May 2021 and will end in late April 2023.

Source: https://www2.gmu.edu/

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