In a lab at Northwestern University, chemists have reimagined how CRISPR travels. They wrapped the fragile gene-editing toolkit inside a dense sphere of DNA, creating a nanostructure that slips into cells with remarkable efficiency. The new system, published Sept. 5 in the Proceedings of the National Academy of Sciences, boosted CRISPR’s ability to enter human and animal cells threefold compared to standard delivery methods and reduced toxicity in the process.
The Problem of Delivery
CRISPR can disable rogue genes, fix harmful mutations, or add new cellular functions. But it cannot enter a cell by itself. Scientists have relied on viruses and lipid nanoparticles to do the job, but each comes with drawbacks. Viruses are efficient, but they provoke immune responses. Lipid particles are safer, but they often get trapped inside cellular compartments, leaving the gene-editing tools stranded.
“Only a fraction of the CRISPR machinery actually makes it into the cell and even a smaller fraction makes it all the way into the nucleus,” said Northwestern chemist Chad A. Mirkin.
A DNA-Wrapped Taxi
Mirkin’s team turned to spherical nucleic acids (SNAs), a form of DNA arranged in globular shells rather than linear strands. These structures, roughly 50 nanometers in diameter, naturally slip into cells, and they can be engineered to target specific tissues. Seven SNA-based therapies are already in clinical trials, a hint of their versatility. By decorating lipid nanoparticle cores with a DNA coating, the researchers built hybrid carriers, dubbed LNP-SNAs, that could transport Cas9 enzymes, guide RNAs, and DNA repair templates directly into cells.
“Simple changes to the particle’s structure can dramatically change how well a cell takes it up,” Mirkin said. “The SNA architecture is recognized by almost all cell types, so cells actively take up the SNAs and rapidly internalize them.”
Boosting CRISPR Across Cell Types
When the team tested the new vehicles in skin cells, kidney cells, bone marrow stem cells, and white blood cells, the results were striking. LNP-SNAs entered cells up to three times more effectively than traditional lipid particles, caused far less toxicity, and increased precise DNA repair by more than 60 percent. In every metric, they outperformed existing CRISPR delivery platforms.
Mirkin and colleagues now plan to validate the system in disease models, while Flashpoint Therapeutics, a Northwestern spinout, works to advance the technology toward clinical trials. The strategy is modular, meaning it could be adapted for a wide range of therapeutic applications, from blood disorders to cancer.
CRISPR’s future hinges not only on its ability to cut and repair DNA but also on whether it can be delivered safely into the right cells at the right time. In this sense, the DNA wrapping is not decoration, but direction. It tells CRISPR where to go. And if this system succeeds, it may finally move CRISPR closer to fulfilling its long-promised role in medicine.
Explainer: What Are Spherical Nucleic Acids?
Spherical nucleic acids (SNAs) are tiny structures where DNA or RNA strands are densely arranged around a nanoparticle core, forming a globe-like shape. Unlike linear genetic material, SNAs are readily absorbed by most cell types without the need for additional carriers. This makes them valuable for delivering drugs, vaccines, and, in this case, CRISPR gene-editing machinery. Their DNA shell can also be programmed to guide the particles to specific tissues or organs, increasing precision and reducing side effects. SNAs are already being tested in human clinical trials for cancer and skin disease therapies.
Journal: Proceedings of the National Academy of Sciences
DOI: 10.1073/pnas.2426094122
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