Framework for nanoscale material design using programmable DNA systems enables precise control over structure, function, and immune signaling in soft materials.
(Nanowerk Spotlight) Nucleic acids offer programmable, self-assembling platforms for biomedical design, capable of mimicking cellular processes and revealing mechanisms of molecular organization.
Many cell types use biomolecular condensates—formed through liquid–liquid phase separation of proteins and nucleic acids—to concentrate specific molecules and control reactions without membranes. These structures support rapid cellular adaptation by generating localized biochemical environments.
A collaborative research team comprising the Afonin Lab at UNC Charlotte, the Yingling and LeBlanc Labs at NC State University, and the Krasnoslobodtsev Lab at the University of Nebraska Omaha synthesized and modeled biomolecular condensates.
“We used biotinylated DNA strands to crosslink streptavidin-coated quantum dots (QDs), forming 3D biomolecular condensates with predefined morphology, physicochemical properties, immunorecognition, and biological behaviors,” Elizabeth Skelly, first author on the publication, tells Nanowerk.
Experimental workflow of the published work. (Image courtesy of the researchers) (click on image to enlarge)
To predict how molecular-scale design influences material behavior, the team employed Dissipative Particle Dynamics (DPD), a coarse-grained simulation method suitable for modeling soft matter at the mesoscale. DPD simplifies DNA strands and nanoparticles into bead-like units, enabling the study of self-assembly over extended timescales and larger length scales than traditional molecular dynamics.
“Traditional coarse-grained simulations use fixed bonds, limiting their ability to capture dynamic processes like nucleic acid hybridization. We enhanced DPD with a rule-based DyBonding framework in LAMMPS, enabling large-scale reactive simulations of soft materials, validated through experimental collaboration,” explains Christina Bayard, another first author on the published work.
The study modeled two assembly routes: (M1) free-floating double-stranded DNA bridging between particles and (M2) single-stranded DNA tethered to QDs, binding like molecular Velcro. DyBonding allowed dynamic bond formation between biotin on DNA ends and streptavidin on QDs (M1) or complementary DNA strands (M2), a novel addition to standard DPD simulations.
The model provided new insights into nanoscale interactions, revealing that M1 forms larger, rounder, and more compact condensates faster than M2, which produces smaller, dispersed clusters. Microscopy and experimental measurements confirmed these predictions.
The simulations captured key emergent behaviors such as spherical morphology, internal density variations, and structural rearrangements. By incorporating DNA base pairing, electrostatic repulsion, and DNA-nanoparticle interactions, the models aligned with experimental observations and provided a predictive framework for tuning condensate properties before laboratory testing.
Experiments with various DNA lengths and synthesis routes confirmed that morphology, size, and mechanical behavior aligned with simulation predictions. Analysis techniques included gel electrophoresis, fluorescence microscopy, microrheology, and atomic force microscopy.
Immunostimulatory assays using human reporter cells showed that the condensates activate the IRF pathway via cGAS binding to double-stranded DNA. Longer DNA strands enhanced this response. No activation of the NF-κB pathway was observed.
The work provides a framework for nanoscale material design using programmable DNA systems. As DNA nanotechnology advances toward functional, adaptive systems, the ability to simulate and optimize assembly pathways at the molecular level will be crucial for developing programmable, biocompatible materials.
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