Coacervation drives morphological diversity of mRNA encapsulating nanoparticles

The Journal of Chemical Physics, Journal Year: 2025, Volume and Issue: 162(7)

Published: Feb. 19, 2025

The spatial arrangement of components within an mRNA encapsulating nanoparticle has consequences for its thermal stability, which is a key parameter therapeutic utility. mesostructure nanoparticles formed with cationic polymers several distinct putative structures: here, we develop field theoretic simulation model to compute the phase diagram amphiphilic block copolymers that balance coacervation and hydrophobicity as driving forces assembly. We predict morphologies these nanoparticles, depending on salt conditions hydrophobicity. compare our predictions cryogenic-electron microscopy images encapsulated by charge altering releasable transporters. In addition, provide graphics processing unit-accelerated, open-source codebase general purpose simulations, anticipate will be useful tool community.

Language: Английский

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Ionizable Cholesterol Analogs as the Fifth Component of Lipid Nanoparticles for Selective Targeting Delivery of mRNA

ACS Applied Materials & Interfaces, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 13, 2025

Lipid nanoparticles (LNP) have shown great promise in clinical applications for delivering mRNA. Targeted delivery of mRNA to particular tissues or organs is essential precise therapeutic outcomes and minimized side effects various disease models. However, achieving targeted beyond the liver a challenge based on current LNP formulations. In this report, we synthesized four ionizable cholesterol analogs by attaching two tertiary amine groups onto head cholesterol-like structure incorporated them as fifth component into conventional commercial LNPs ALC-0315 SM-102. Selective targeting achieved adjusting proportion LNP. Specifically, spleen-targeted 0315-Ergo-40% formulation demonstrated an impressive 95% efficiency, while lung-targeted 102-Sito-40% up 78%. Moreover, when strategy applied self-developed lipid named U-101 instead SM-102, efficiencies spleen lungs reach 96 71%, respectively. Multiple assessments suggest that inclusion does not compromise stability, indicated consistent particle size, polydispersity index (PDI), encapsulation efficiency. Furthermore, test results kidney function immunogenicity reveal no increase toxicity vivo following introduction component. Additional studies vitro cytotoxicity, lysosomal escape, cellular transfection efficiency confirm diminish performance. Taken together, incorporation leads delivery, which features strong organ selectivity, high safety, suitability further evaluation.

Language: Английский

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Lung‐Specific mRNA Delivery by Ionizable Lipids with Defined Structure‐Function Relationship and Unique Protein Corona Feature

Advanced Science, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 18, 2025

Abstract Targeted delivery of mRNA with lipid nanoparticles (LNPs) holds great potential for treating pulmonary diseases. However, the lack rational design principles efficient lung‐homing lipids hinders prevalence therapeutics in this organ. Herein, combinatorial screening structure‐function analysis is applied to rationalize strategy nonpermanently charged lung‐targeted ionizable lipids. It discovered that carrying N‐methyl and secondary amine groups heads, three tails originated from epoxyalkanes, exhibiting superior selectivity efficiency. Representative systematically variation chemical structures are selected study well‐known but still puzzling “protein corona” adsorbed on surface LNPs. In addition commonly used corona‐biomarker vitronectin, other arginine‐glycine‐aspartic acid (RGD)‐rich proteins usually involved collagen‐containing extracellular matrix, such as fibrinogen fibronectin have also been identified a strong correlation lung tropism. This work provides insight into lung‐targeting reveals previously unreported function RGD‐rich protein corona

Language: Английский

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Multivalent ionizable lipid-polypeptides for tumor-confined mRNA transfection

Bioactive Materials, Journal Year: 2025, Volume and Issue: 46, P. 423 - 433

Published: Jan. 5, 2025

Language: Английский

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In vivomRNA delivery to the lung vascular endothelium by dicationic Charge-Altering Releasable Transporters

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: April 19, 2025

Abstract Endothelial cells (EC) comprise the pulmonary vascular bed and play a significant role in health disease. Consequently, EC niche represents an attractive therapeutic target for treating wide range of diseases. We have identified new class dicationic Charge-Altering Releasable Transporters. These single-component transporters selectively deliver mRNA to lung upon intravenous administration without use targeting ligand. Significantly, number spatial array cationic charges within repeating units CART polymer are found control both delivery efficacy tissue tropism. High-resolution imaging revealed efficient endothelial arteries, veins capillaries. The selective tropism these CARTs, coupled with tunable synthesis this family amphiphiles, enabling platform research clinical applications.

Language: Английский

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