Bridging the Gap: Computational Insights Unlock LNP-Immune System Mysteries

The clinical translation of gene therapies has long been hindered by a grand singular challenge: delivery. To overcome this obstacle, researchers have created potent materials that convey genetic messages to cells with high specificity. Through rational design, combinatorial high-throughput screening, and other strategies, lipid nanoparticles (LNPs) emerged as the preferred delivery vehicles for nucleic acids. However, the quest for efficacy inadvertently overshadowed a critical question – how do these LNPs interact with the immune system?
Understanding the immune response of RNA delivery vehicles would not only mitigate side effects but also allow us to select potent materials tailor-made for specific applications. For delivery to the liver or lung, an immunoquiescent structure might be best suited. In contrast, a formulation that rallies immune cells might be the ideal choice for fighting cancer. However, fundamental mechanisms governing LNP-immune interactions are mostly unknown, and a toolbox linking LNP structure to its immunogenicity and downstream effector responses has been elusive.
To fill this critical knowledge gap, we designed a small library of LNPs that we probed for immune responses. These experiments were conducted in mice at Carnegie Mellon as well as in human donor cells at IIT Bombay with the help of our collaborators. As with many scientific endeavors, the initial stages yielded confusion, as the data seemed chaotic. There were no clear trends or patterns in either mice or humans, leaving us puzzled.
During this period of uncertainty, the COVID-19 pandemic emerged, bringing with it a global focus on LNPs. Suddenly, LNPs took center stage in our response to the pandemic and the questions we had been grappling with took on new urgency and relevance. As reports of vaccine-associated adverse reactions surfaced, we wondered: Why are these vaccines causing side effects in some people? If we knew the underlying mechanisms, could we have designed less painful ones?
The real-world implications of our work, the puzzling data, and the pandemic-induced lockdown catalyzed a new approach. We turned to computational simulations to study nanoparticle-cell interactions at molecular resolution. Strikingly, these simulations led to an intriguing observation: the amine headgroups of the lipids were interacting with receptors and membranes in a manner that explained their immune responses. This computational detour provided a new perspective on our experimental data, suggesting that the key to understanding the immune responses might lie in these head group characteristics. Eager to validate our computational findings, we re-designed experiments focusing specifically on the relationship between immune responses and lipid headgroups. To our excitement, we identified receptors that recognized our lipids. The studies also confirmed our hypothesis: the immune responses were indeed strongly dependent on the structure of the amine headgroups. Drawing from our knowledge, we designed vehicles that overcame efficacy loss after repeat dosing – a poorly understood adversity long observed with many lipid-based particles.
This discovery has significant implications for the field of RNA delivery. Our nuanced approach provides a framework that can be incorporated into decision trees while designing lipids or selecting formulations. Further, our findings may contribute to the ongoing efforts to design safer and more efficient delivery systems with predictable immunological effects, possibly improving treatment approaches.
Finally, we believe our journey illustrates how unexpected challenges, like a pandemic-induced lab shutdown, can lead to fresh perspectives. More importantly, it underscores the transformative power of interdisciplinary approaches and highlights the exciting possibilities that emerge when we follow our scientific curiosity.
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You can read the paper at:
Chaudhary, N., Kasiewicz, L.N., Newby, A.N. et al. Amine headgroups in ionizable lipids drive immune responses to lipid nanoparticles by binding to the receptors TLR4 and CD1d. Nat. Biomed. Eng (2024). https://doi.org/10.1038/s41551-024-01256-w
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