Northwestern University researchers have developed a new nanostructure that improves the delivery of CRISPR gene-editing tools into cells. The innovation, called lipid nanoparticle spherical nucleic acids (LNP-SNAs), packages the full set of CRISPR components inside a protective DNA shell. This design allows the particles to enter cells up to three times more effectively than standard lipid nanoparticles and reduces toxicity.
The research team, led by Chad A. Mirkin, tested LNP-SNAs in various human and animal cell types. Results showed not only increased cellular uptake but also a threefold boost in gene-editing efficiency and over 60% improvement in precise DNA repairs compared to current methods. These findings were published on September 4 in the Proceedings of the National Academy of Sciences.
Mirkin explained the challenge facing CRISPR-based therapies: “CRISPR is an incredibly powerful tool that could correct defects in genes to decrease susceptibility to disease and even eliminate disease itself,” he said. “But it’s difficult to get CRISPR into the cells and tissues that matter. Reaching and entering the right cells — and the right places within those cells — requires a minor miracle. By using SNAs to deliver the machinery required for gene editing, we aimed to maximize CRISPR’s efficiency and expand the number of cell and tissue types that we can deliver it to.”
Current delivery systems rely on viral vectors or traditional lipid nanoparticles. Viruses are efficient at entering cells but can trigger immune responses, while lipid nanoparticles are safer but less effective because they often become trapped inside cellular compartments.
“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,” Mirkin said. “Another strategy is to remove cells from the body, inject the CRISPR components and then put the cells back in. As you can imagine, that’s extremely inefficient and impractical.”
To address these issues, Mirkin’s team used SNAs—globular forms of DNA or RNA invented at Northwestern—to coat their LNPs with short strands of DNA. This approach helps target specific cell types through engineered sequences while increasing absorption by most cell types.
“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.”
In laboratory tests involving skin cells, white blood cells, bone marrow stem cells, and kidney cells, LNP-SNAs demonstrated high efficiency across several metrics: uptake by target cells, low toxicity levels, successful gene delivery, and effective genetic modification.
Looking ahead, Mirkin plans further validation in disease models using animals before moving toward clinical trials through Flashpoint Therapeutics—a Northwestern biotechnology spin-out commercializing this technology.
“CRISPR could change the whole field of medicine,” Mirkin said. “But how we design the delivery vehicle is just as important as the genetic tools themselves. By marrying two powerful biotechnologies — CRISPR and SNAs — we have created a strategy that could unlock CRISPR’s full therapeutic potential.”
The study received support from agencies including the Air Force Office of Scientific Research (award number FA9550-22-1-0300), National Science Foundation (award number DMR-2428112), and Edgar H. Bachrach through his foundation.
Mirkin has financial interests in Flashpoint Therapeutics; Northwestern University also holds financial interests in this company.