A DNA origami device capable of inducing tumour cell death
Implementing molecular technology-based strategies to treat cancer can be tricky. Because tumorous tissue cells are highly similar to healthy cells at a molecular level, most approaches are linked to high risks of unspecific and undesired effects on healthy tissues and organs.
While this challenge still exists, hope is growing thanks to a promising development in DNA nanotechnology: DNA origami devices.
Nanorobots explained
In these novel structures, DNA oligonucleotides (i.e. short DNA chains) serve an unorthodox role as the building material of nanorobotic molecular switches that specifically activate to eliminate tumour cells while leaving healthy cells intact. But how is this specificity achieved?
The key to this finding is the rational design of nanoscale structures with unprecedented resolution using DNA oligonucleotides as building blocks, in contrast to their more conventional role as genetic material. This way, the specific chemical interactions that are the heart of the DNA structure are exploited to engineer novel three-dimensional forms.
These follow an intentionally chosen design, mimicking the precise folds applied to paper to generate origami figures. Only when encountering solid tumours can these nanorobots expose specific peptide ligands that trigger the death of the cancerous cells by activating the tumour’s programmed cell death response – apoptosis.
Elimination of solid tumours by a pH-sensitive molecular switch
The strategy takes advantage of the distinctive metabolism of solid tumour cells, which consume excessive amounts of oxygen, generating anaerobic environments. At low oxygen pressures, cells carry out anaerobic glycolysis, which produces a drop in the surrounding medium’s pH from the physiological value of 7.4 to a more acidic value of 6.5.
Due to their carefully designed chemical characteristics, the nanorobots can autonomously switch from hiding the peptide ligands at pH 7.4 to displaying those same ligands on their surface at pH 6.5. Next is the interaction of the presented ligands with specific surface receptors of the cancer cell, which are then forced to group. This receptor-clustering phenomenon represents the primary initiation signal for apoptosis.
The DNA origami device was demonstrated to slow tumour growth by 30% when administered intravenously in cancer mouse models. In comparison, direct intratumoural injections were shown to suppress tumours with a 70% efficacy in the same experimental system. Please look at Figure 6 in the manuscript for more details on the device’s biodistribution and in vivo effects.
Not so fast
This work comprises implementing outstanding molecular design methodologies, using highly precise molecular modelling software tools, and achieving a successful proof of concept of the treatment in mice. However, to enhance the study’s accuracy, the next step should involve investigating the device’s use in humanised mouse models.
Why does it matter?
According to the WHO, in 2022, there were an estimated 20 million new cancer cases and 9.7 million deaths worldwide. The WHO highlights: “the growing burden of cancer, the disproportionate impact on underserved populations, and the urgent need to address cancer inequities worldwide.”
Establishing new, efficient and reasonably priced therapies based on the discoveries described in this work could represent a major upgrade in cancer treatments as we know them. As the authors mention, the recent availability of affordable peptide synthesis services could aid in scaling up the production of these devices for future therapeutic testing.
Take home messages
1. A novel cancer treatment therapy is under development, which uses DNA nanostructures as intelligent devices (or nanorobots) that identify and eliminate solid tumours.
2. These nanorobots have been successfully tested in cancer mouse models.
3. Further work must be done to complete the characterisation of this treatment, including testing the device in humanised mouse models.
1. A novel cancer treatment therapy is under development, which uses DNA nanostructures as intelligent devices (or nanorobots) that identify and eliminate solid tumours.
2. These nanorobots have been successfully tested in cancer mouse models.
3. Further work must be done to complete the characterisation of this treatment, including testing the device in humanised mouse models.
Guest author: Celina Galles, PhD
Reviewer: Barbara Fahmy, MS OTR, MPA
This article was written as part of a series of ‘journal club’ summaries for Scientific Writers Ltd and is based on the following publication.
Title: A DNA robotic switch with regulated autonomous display of cytotoxic ligand nanopatterns
First Author: Wang Y, et al.
Journal: Nature Nanotechnology
Date online: 01 July 2024
Additional References:
Cancer. World Health Organization. 2024. Available at: https://www.who.int/health-topics/cancer#tab=tab_1. Accessed October 17, 2024.
Global cancer burden growing, amidst mounting need for services. World Health Organization. February 1, 2024. Accessed October 17, 2024. https://www.who.int/news/item/01-02-2024-global-cancer-burden-growing–amidst-mounting-need-for-services
