CRISPR holds the potential to rewrite the genetic code behind countless diseases, offering the promise of revolutionizing medicine. However, the challenge remains: how to safely and efficiently deliver CRISPR’s gene-editing machinery into the relevant cells and tissues.
Now, Northwestern University chemists have developed a groundbreaking nanostructure that could dramatically improve CRISPR delivery and expand its therapeutic potential.
These lipid nanoparticle spherical nucleic acids (LNP-SNAs) deliver CRISPR’s tools—such as the Cas9 enzyme, guide RNA, and DNA repair templates—inside a dense, protective DNA shell. This new design not only shields the cargo but also enhances its ability to target specific organs and cells.
In lab tests across various human and animal cells, LNP-SNAs were up to three times more effective at entering cells compared to traditional lipid particle delivery systems used in COVID-19 vaccines.
Additionally, the technology reduced toxicity, increased gene-editing efficiency, and improved DNA repair success rates by more than 60%.
These findings, published in Proceedings of the National Academy of Sciences, could pave the way for safer, more reliable gene therapies and advance the field of structural nanomedicine, a discipline pioneered by Chad A. Mirkin and pursued by scientists globally.
Overcoming Delivery Challenges in CRISPR Technology
CRISPR-based therapies have immense potential, but one major hurdle remains: getting the CRISPR machinery inside the target cells, particularly the cell nucleus where gene editing occurs. Currently, researchers use viral vectors or lipid nanoparticles (LNPs) to deliver CRISPR components.
- Viral vectors are efficient but can provoke immune responses, leading to side effects.
- Lipid nanoparticles are safer but inefficient, often getting trapped in endosomes (cellular compartments) before releasing their genetic cargo.
“Only a fraction of the CRISPR machinery actually makes it into the cell, and even fewer reach the nucleus,” said Mirkin, who led the study. “This inefficiency is a major roadblock for CRISPR-based therapies.”
The Role of Lipid Nanoparticle Spherical Nucleic Acids (LNP-SNAs)
To overcome this barrier, Mirkin’s team turned to spherical nucleic acids (SNAs)—nanostructures that combine DNA and RNA to create globular forms of genetic material. These particles, roughly 50 nanometers in diameter, can enter cells more effectively than linear forms of DNA or RNA.
In this study, the researchers began with a lipid nanoparticle core that carried the CRISPR machinery. They then wrapped the core in a dense layer of short DNA strands.
The DNA coating helps the particles interact with specific cell surface receptors, making them easier to absorb. The DNA also enables customization to target specific cell types, enhancing the precision of CRISPR delivery.
“Simple changes to the particle’s structure can dramatically change how well a cell takes it up,” Mirkin explained. “The SNA architecture is recognized by almost all cell types, so they actively absorb and internalize the particles.”
Boosting CRISPR Efficiency Across Multiple Cell Types
Mirkin and his team tested the LNP-SNAs in a variety of human and animal cell cultures, including skin cells, white blood cells, human bone marrow stem cells, and human kidney cells.
They evaluated how efficiently the cells internalized the particles, how toxic they were, and whether the particles successfully delivered CRISPR components for gene editing.
The results were striking. The new delivery system enabled efficient CRISPR editing, significantly improving DNA repair and the ability to make complex genetic modifications. The LNP-SNAs demonstrated far less toxicity compared to traditional lipid-based systems.
“Our system dramatically boosted CRISPR efficiency and reduced potential side effects, opening the door for safer and more effective genetic therapies,” said Mirkin.
A Modular Platform for Broader Applications
Looking ahead, Mirkin and his team plan to validate the LNP-SNA delivery system in multiple in vivo disease models. The platform’s modular design allows researchers to adapt it for various therapeutic applications, from treating genetic diseases to cancer.
Northwestern biotechnology spin-out Flashpoint Therapeutics is commercializing the technology, with plans to move it rapidly toward clinical trials. The potential applications of this breakthrough are vast, and the team is excited to see how this new approach can expand CRISPR’s therapeutic reach.
“By combining two powerful biotechnologies—CRISPR and SNAs—we’ve created a strategy that could unlock CRISPR’s full therapeutic potential,” Mirkin said.
The Future of CRISPR and Nanomedicine
This study highlights the importance of designing delivery vehicles that complement powerful gene-editing tools like CRISPR. As CRISPR-based therapies move closer to clinical use, improving delivery methods will be just as critical as advancing the editing technology itself.
Mirkin’s team is optimistic that their work will contribute to the next generation of gene therapies, enabling scientists to treat a wide range of diseases with greater precision and efficiency.
The research was supported by the Air Force Office of Scientific Research, the National Science Foundation, and Edgar H. Bachrach through the Bachrach Foundation. Mirkin has financial interests in and affiliations with Flashpoint Therapeutics, which is commercializing this technology.
