Novel Biodegradable Class of Ionizable Lipids for Efficient RNA Delivery

The presentation will focus on a comparative analysis of biodegradable and non-biodegradable ionizable lipids for RNA delivery via lipid nanoparticles (LNPs). Biodegradable lipids have shown potential as effective RNA delivery platforms through LNP formation. Their elimination post-delivery reduces the risk of adverse effects associated with both the lipid and the payload. Furthermore, novel lipid structures may enable extrahepatic payload delivery and facilitate elimination from non-target organs, thereby improving delivery efficiency and minimizing off-target effects. Due to their rapid elimination, biodegradable lipids may also support repeated dosing at shorter intervals.

In this study, various classes of biodegradable lipids were designed and optimized by modifying chain lengths, groups and bonds.

To evaluate the performance of these lipids, we developed a high-throughput workflow. The process began with prioritizing formulation and particle characteristics to determine developability, followed by cell-based screening. Promising lipid candidates were then tested in animal models to assess RNA delivery efficiency, tissue distribution, and organ clearance.

Compared to MC-3, a non-biodegradable lipid, biodegradable lipids exhibited lower RNA delivery efficiency when measured by total expression, likely due to their inherent degradable nature. However, these lipids demonstrated broader tissue distribution, favorable expression, and efficient clearance. Importantly, they showed negligible liver enzyme increases at higher doses, comparable to naïve mice. In contrast, MC-3 LNPs caused elevated enzyme levels and histological changes even at lower doses. Notably, a strong expression may not always be necessary, depending on the therapeutic application or target, making these biodegradable lipids viable candidates for repeated dosing.