Northwestern University researchers have developed a breakthrough nanostructure that significantly enhances the delivery and safety of CRISPR gene-editing technology, potentially unlocking new therapeutic possibilities for treating a wide range of diseases. The study, published in the Proceedings of the National Academy of Sciences, demonstrates how combining two biotechnologies can overcome major limitations in current CRISPR delivery methods.
Enhanced Delivery Through Novel Nanostructure Design
The research team, led by Chad Mirkin at Northwestern University's International Institute for Nanotechnology, created lipid nanoparticle spherical nucleic acids (LNP-SNAs) that carry the complete CRISPR gene-editing toolkit. These nanostructures feature a lipid nanoparticle core loaded with Cas9 enzymes, guide RNA, and DNA repair templates, surrounded by a dense protective shell of short DNA strands.
"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 explained. "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."
The spherical nucleic acids (SNAs) architecture addresses key limitations of existing delivery methods. While viral vectors can trigger unwanted immune responses and lipid nanoparticles often get trapped in cellular compartments, the LNP-SNA design enables more efficient cellular uptake and therapeutic material release.
Significant Performance Improvements Across Cell Types
Laboratory testing across multiple human and animal cell types—including skin cells, white blood cells, human bone marrow stem cells, and kidney cells—revealed substantial improvements over standard delivery methods. The LNP-SNA approach demonstrated:
- Up to three times more effective cellular entry compared to standard lipid nanoparticle systems
- Significantly reduced cellular toxicity
- Threefold enhancement in gene-editing efficiency
- More than 60% improvement in precise DNA repair success rates
"Simple changes to the particle's structure can dramatically change how well a cell takes it up," Mirkin noted. "The SNA architecture is recognized by almost all cell types, so cells actively take up the SNAs and rapidly internalize them."
Targeted Delivery and Therapeutic Potential
The DNA coating layer serves dual purposes: protecting CRISPR components and directing tissue-specific targeting. This capability allows researchers to control which organs and tissues the LNP-SNAs migrate to, potentially enabling more precise therapeutic interventions.
"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."
Commercial Development and Future Applications
Flashpoint Therapeutics, a clinical-stage biotechnology company, holds exclusive global licensing rights to the technology and plans to advance it toward clinical trials. The company's CEO, Barry Labinger, emphasized the platform's potential for creating treatments across various diseases through collaborations with other companies.
"CRISPR is an incredibly powerful tool that could correct defects in genes to decrease susceptibility to disease and even eliminate disease itself," said Mirkin, who serves as Scientific Founder of Flashpoint Therapeutics. "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."
The research team plans to validate their LNP-SNA approach in multiple in vivo disease models and adapt the technology for various therapeutic applications. The advancement represents a significant step toward making CRISPR-based therapies safer and more effective for clinical use.
