Lipid nanoparticles (LNPs) have enormous potential for the delivery of genomic medicine. One obstacle, however, is the lack of effective ways to target specific cell types. In order to target lung cells, the identification of chemically distinct lipid libraries would first be necessary.

Now, a team of engineers at the University of Pennsylvania led by Michael Mitchell, PhD, associate professor in the department of bioengineering, has developed a new means of targeting the lungs with LNPs. More specifically, they report the implementation “of a barcoded high-throughput screening system as a means to identify the lung-targeting efficacy of cationic, degradable lipid-like materials.”

The findings demonstrate a new method for efficiently determining which LNPs are likely to bind to the lungs, rather than the liver. “The way the liver is designed,” said Mitchell, “LNPs tend to filter into hepatic cells, and struggle to arrive anywhere else. Being able to target the lungs is potentially life-changing for someone with lung cancer or cystic fibrosis.”

This is published in Nature Communications in the paper, “High-throughput barcoding of nanoparticles identifies cationic, degradable lipid-like materials for mRNA delivery to the lungs in female preclinical models.

Previous studies have shown that cationic lipids are more likely to successfully deliver their contents to lung tissue. “However, the commercial cationic lipids are usually highly positively charged and toxic,” said Lulu Xue, PhD, a postdoctoral fellow in the Mitchell Lab.

Typically, it would require hundreds of mice to individually test the members of a library of LNPs to find one with a low charge that has a higher likelihood of delivering a medicinal payload to the lungs.

Instead, the team used barcoded DNA to tag each LNP with a unique strand of genetic material. More specifically, they combinatorially synthesized 180 cationic, degradable lipids. Then, they used barcoding technology to quantify how the selected 96 distinct lipid nanoparticles deliver DNA barcodes in vivo.

After identifying an LNP that successfully penetrated lung cells—the top-performing nanoparticle formulation delivering Cas9-based genetic editors—they were administered to a lung tumor model in female mice.

The treatment had a positive effect, drastically reducing tumor size by delivering a strand of mRNA and gRNA that suppresses the growth of lung tumors. “This technology will help to accelerate the development of mRNA therapeutics beyond the liver,” said Xue, pointing to the speed, low cost, and efficacy of the technique.

The authors wrote that the data demonstrate that “employing high-throughput barcoding technology as a screening tool for identifying nanoparticles with lung tropism holds potential for the development of next-generation extrahepatic delivery platforms.”

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