Predictive Lung- and Spleen-Targeted mRNA Delivery with Biodegradable Ionizable Lipids in Four-Component LNPs DOI Creative Commons

Juan Heredero,

Álvaro Peña, Esther Broset

et al.

Pharmaceutics, Journal Year: 2025, Volume and Issue: 17(4), P. 459 - 459

Published: April 2, 2025

Background/Objectives: Lipid nanoparticles (LNPs) are leading mRNA delivery vehicles, with ionizable lipids (ILs) as their key component. However, the relationship between IL structure and LNP endogenous organ-targeting is not well understood. In this study, we developed a novel library of biodegradable ILs featuring beta-propionate linkers, which, when incorporated into four-component formulation, show excellent extrahepatic selectivity high protein expression. Methods: We explored impact structural modifications in hydrophobic chains polar-head groups while keeping linkers unchanged. vivo results were evaluated to examine how changes influence biodistribution spleen or lungs. formulations assessed for expression levels organ-specific targeting. Additionally, corona formation by best-performing LNPs was examined provide further mechanistic insights. Results: Organ targeting significantly influenced ILs, allowing precise control Branched demonstrated higher propensity targeting, group could drastically shift from lung spleen. This led identification LNPs’ zeta potential determinant properties. Notably, lipid A3T2C7, also known CP-LC-1495, displayed strong (97%) tissue (1.21 × 108 p/s). Similarly, several promising candidates spleen-targeting exceeding 1 107 p/s (selectivity >80%). Conclusions: study elucidates structure–function relationships passive delivery, highlighting fine-tuning chains, groups, surface charge (zeta potential) allows biodistribution, mechanism formation. These findings enable rational design targeted systems, enhancing therapeutic specific organs, such

Language: Английский

Predictive Lung- and Spleen-Targeted mRNA Delivery with Biodegradable Ionizable Lipids in Four-Component LNPs DOI Creative Commons

Juan Heredero,

Álvaro Peña, Esther Broset

et al.

Pharmaceutics, Journal Year: 2025, Volume and Issue: 17(4), P. 459 - 459

Published: April 2, 2025

Background/Objectives: Lipid nanoparticles (LNPs) are leading mRNA delivery vehicles, with ionizable lipids (ILs) as their key component. However, the relationship between IL structure and LNP endogenous organ-targeting is not well understood. In this study, we developed a novel library of biodegradable ILs featuring beta-propionate linkers, which, when incorporated into four-component formulation, show excellent extrahepatic selectivity high protein expression. Methods: We explored impact structural modifications in hydrophobic chains polar-head groups while keeping linkers unchanged. vivo results were evaluated to examine how changes influence biodistribution spleen or lungs. formulations assessed for expression levels organ-specific targeting. Additionally, corona formation by best-performing LNPs was examined provide further mechanistic insights. Results: Organ targeting significantly influenced ILs, allowing precise control Branched demonstrated higher propensity targeting, group could drastically shift from lung spleen. This led identification LNPs’ zeta potential determinant properties. Notably, lipid A3T2C7, also known CP-LC-1495, displayed strong (97%) tissue (1.21 × 108 p/s). Similarly, several promising candidates spleen-targeting exceeding 1 107 p/s (selectivity >80%). Conclusions: study elucidates structure–function relationships passive delivery, highlighting fine-tuning chains, groups, surface charge (zeta potential) allows biodistribution, mechanism formation. These findings enable rational design targeted systems, enhancing therapeutic specific organs, such

Language: Английский

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