Xiaowei Liu examines cells to test whether DNA nanostructures could reside comfortably within the appropriate compartment of the cells and be stable for several hours—long enough to set in motion an immune cascade. |
In a quest to make safer and more
effective vaccines, scientists at the Biodesign Institute at Arizona State
University have turned to a promising field called DNA nanotechnology to make
an entirely new class of synthetic vaccines.
In a study published in Nano
Letters, Biodesign immunologist Yung Chang joined forces with her
colleagues, including DNA nanotechnology innovator Hao Yan, to develop the
first vaccine complex that could be delivered safely and effectively by
piggybacking onto self-assembled, 3D DNA nanostructures.
“When Hao treated DNA not as a
genetic material, but as a scaffolding material, that made me think of possible
applications in immunology,” said Chang, an associate professor in the School
of Life Sciences and a researcher in the Biodesign Institute’s Center for Infectious
Diseases and Vaccinology. “This provided a great opportunity to try to use
these DNA scaffolds to make a synthetic vaccine.”
“The major concern was: Is it
safe? We wanted to mimic the assembly of molecules that can trigger a safe and
powerful immune response in the body. As Hao’s team has developed a variety of
interesting DNA nanostructures during the past few years, we have been
collaborating more and more with a goal to further explore some promising human
health applications of this technology.”
The core multidisciplinary
research team members also included: ASU chemistry and biochemistry graduate
student and paper first author Xiaowei Liu, visiting professor Yang Xu,
chemistry and biochemistry assistant professor Yan Liu, School of Life Sciences
undergraduate Craig Clifford and Tao Yu, visiting graduate student from Sichuan
University.
Chang points out that vaccines
have led to the some of the most effective public health triumphs in all of
medicine. The state-of-the-art in vaccine development relies on genetic
engineering to assemble immune system stimulating proteins into virus-like
particles (VLPs) that mimic the structure of natural viruses—minus the harmful
genetic components that cause disease.
DNA nanotechnology, where the
molecule of life can be assembled into 2D and 3D shapes, has an advantage of
being a programmable system that can precisely organize molecules to mimic the
actions of natural molecules in the body.
“We wanted to test several
different sizes and shapes of DNA nanostructures and attach molecules to them
to see if they could trigger an immune response,” said Yan, the Milton D. Glick
Distinguished Chair in the Department of Chemistry and Biochemistry and
researcher in Biodesign’s Center for Single Molecule Biophysics. With their
biomimicry approach, the vaccine complexes they tested closely resembled
natural viral particles in size and shape.
As proof of concept, they
tethered onto separate pyramid-shaped and branched DNA structures a model
immune stimulating protein called streptavidin (STV) and immune response
boosting compound called an adjuvant (CpG oligo-deoxynucletides) to make their
synthetic vaccine complexes.
First, the group had to prove
that the target cells could gobble the nanostructures up. By attaching a
light-emitting tracer molecule to the nanostructures, they found the
nanostructures residing comfortably within the appropriate compartment of the
cells and stable for several hours—long enough to set in motion an immune
cascade.
Next, in a mouse challenge, they
targeted the delivery of their vaccine cargo to cells that are first responders
in initiating an effective immune response, coordinating interaction of
important components, such as: antigen presenting cells, including macrophages,
dendritic cells, and B cells. After the cargo is internalized in the cell, they
are processed and “displayed” on the cell surface to T cells, white blood cells
that play a central role in triggering a protective immune response. The T
cells, in turn, assist B cells with producing antibodies against a target
antigen.
To properly test all variables,
they injected: 1) the full vaccine complex, 2) STV (antigen) alone, 3) the CpG
(adjuvant) mixed with STV.
Over the course of 70 days, the
group found that mice immunized with the full vaccine complex developed a more
robust immune response up to 9-fold higher than the CpG mixed with STV. The
pyramid (tetrahedral)-shaped structure generated the greatest immune response.
Not only was immune response to the vaccine complex specific and effective, but
also safe, as the research team showed, using two independent methods, that no
immune response triggered from introducing the DNA platform alone.
“We were very pleased,” said
Chang. “It was so nice to see the results as we predicted. Many times in
biology we don’t see that.”
With the ability to target
specific immune cells to generate a response, the team is excited about the
prospects of this new platform. They envision applications where they could
develop vaccines that require multiple components, or customize their targets
to tailor the immune response.
Furthermore, there is the
potential to develop targeted therapeutics in a similar manner as some of the
new generation of cancer drugs.
Overall, though the field of DNA
is still young, the research is advancing at a breakneck pace toward translational
science that is making an impact on health care, electronics, and other
applications.
While Chang and Yan agree that
there is still much room to explore the manipulation and optimization of the
nanotechnology, it also holds great promise. “With this proof of concept, the
range of antigens that we could use for synthetic vaccine develop is really
unlimited,” said Chang.
Source: Arizona State University
Filed Under: Drug Discovery
