Researchers discover lipid nanoparticle that delivers mRNA to muscles, avoids other tissues

A team of researchers from the Leslie Dan Faculty of Pharmacy at the University of Toronto discovered an ionizable lipid nanoparticle that delivers mRNA to muscles while avoiding other tissues.

The study, conducted by Assistant Professor Bowen Li and published in the Proceedings of the National Academy of Sciences, also demonstrated that mRNA supplied via lipid nanoparticles elicited robust cellular-level immune responses – a proof-of-concept that could lead to the development of a potential melanoma cancer vaccine.

The novel lipid nanoparticle, known as iso-A11B5C1, exhibits remarkable mRNA transport efficiency in muscle tissues while simultaneously decreasing unwanted mRNA translation in organs such as the liver and spleen. Furthermore, even with low expression in lymph nodes, intramuscular delivery of mRNA packaged with this nanoparticle elicited powerful cellular immune responses.

“Our study showcases for the first time that mRNA lipid nanoparticle can still effectively stimulate a cellular immune response and produce robust anti-tumor effects, even without direct targeting or transfecting lymph nodes,” he said.

“This finding challenges conventional understandings and suggests that high transfection efficiency in immune cells may not be the only path to developing effective mRNA vaccines for cancer.”

Lipid nanoparticles, or LNPs, are critical for delivering mRNA-based therapeutics, such as COVID-19 mRNA vaccinations, which were utilized globally during the last pandemic. Many LNP designs, however, can accidentally result in significant mRNA expression in off-target tissues and organs such as the liver or heart, resulting in typically curable but undesirable side effects. According to Li, a recent recipient of the Gairdner Early Career Investigator Award, the desire to improve the safety of mRNA treatments with the potential to treat a wide range of disorders means there is an urgent need for LNPs engineered to limit these off-target effects.

According to the latest findings, iso-A11B5C1 displayed a high level of muscle-specific mRNA delivery effectiveness when compared to the existing benchmark LNP created by the Massachusetts-based biotechnology company Moderna. It also elicited a different type of immune response than vaccines used to treat infectious disorders.

“Iso-A11B5C1 elicited a comparable cellular immune response despite eliciting a lower humoral immune response, which is typically central to current antibody-focused vaccines.” This discovery prompted Li’s team to investigate it further as a potential cancer vaccine candidate in a melanoma model where cellular immunity is important.

Jingan Chen, a PhD trainee from the Institute of Biomedical Engineering, and Yue Xu, a postdoctoral researcher in the Li lab and a research fellow affiliated with PRiME, a U of T institutional strategic program, were part of the study’s interdisciplinary research team.

“Although iso-A11B5C1 showed limited capacity to trigger humoral immunity, it effectively initiated cellular immune responses through intramuscular injection,” Chen added. “The substantial anti-tumor effects observed with iso-A11B5C1 underscore its promise as a viable candidate for cancer vaccine development.”

The new platform enables faster and more precise lipid design

The researchers discovered iso-A11B5C1 by employing an innovative technology designed to rapidly generate a variety of chemically varied lipids for further testing. This technology, which was recently unveiled as part of the study, solves multiple hurdles by expediting the process of producing ionizable lipids with a high potential for translation into therapeutics.

Within 12 hours, hundreds to thousands of chemically varied ionizable lipids can be produced by rapidly joining three separate functional groups.

“Here we report a powerful strategy to synthesize ionizable liquids in a one-step chemical reaction,” he stated. “This new platform provides new insights that could help guide lipid design and evaluation processes going forward and allows the field to tackle challenges in RNA delivery with a new level of speed, precision and insight.”

Source Link