Low Molecular Weight Alginate Oligosaccharides as Alternatives to PEG for Enhancement of the Diffusion of Cationic Nanoparticles Through Cystic Fibrosis Mucus

Airway mucus is a major barrier to the delivery of lipid‐based nanoparticles in chronic airway diseases such as cystic fibrosis (CF). Receptor‐Targeted Nanocomplexes (RTN), comprise mixtures of cationic lipids and bifunctional peptides with receptor‐targeting and nucleic acid packaging properties. T...

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Veröffentlicht in:Advanced healthcare materials 2025-01, Vol.14 (1), p.e2400510-n/a
Hauptverfasser: Maeshima, Ruhina, Tagalakis, Aristides D., Gyftaki‐Venieri, Dafni, Jones, Stuart A., Rye, Philip D., Tøndervik, Anne, Åstrand, O. Alexander H., Hart, Stephen L.
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Sprache:eng
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Zusammenfassung:Airway mucus is a major barrier to the delivery of lipid‐based nanoparticles in chronic airway diseases such as cystic fibrosis (CF). Receptor‐Targeted Nanocomplexes (RTN), comprise mixtures of cationic lipids and bifunctional peptides with receptor‐targeting and nucleic acid packaging properties. The aim of this study is to improve the mucus‐penetrating properties of cationic siRNA and mRNA RTNs by combining them with low molecular weight alginate oligosaccharides, OligoG and OligoM. Cationic RTNs formulated with either alginate become strongly anionic, while PEGylated messenger RNA (mRNA) and short interfering RNA (siRNA) RTNs remain cationic. Both alginates enhance mucus diffusion rates of cationic siRNA and mRNA RTNs in a static mucus barrier diffusion model, with OligoG particularly effective. PEGylation also enhance mucus diffusion rates of siRNA RTNs but not mRNA RTNs. Electron microscopy shows that RTNs remained intact after mucosal transit. The transfection efficiency of OligoM‐coated mRNA RTNs is better than those coated with OligoG or PEG, and similar to cationic RTNs. In siRNA RTN transfections, OligoM is better than OligoG although 1% PEG is slightly better than both. The combination of cationic RTNs and alginate oligosaccharides represents a promising alternative to PEGylation for epithelial delivery of genetic therapies across the mucus barrier while retaining transfection efficiency. Enhanced mucus‐penetration of cationic siRNA and mRNA Receptor‐Targeted Nanocomplexes (RTNs) coated with alginate oligosaccharides (OligoG and OligoM) are demonstrated. Alginate coated cationic RTNs become negatively charged that improves their rate of mucus diffusion, with OligoG being particularly effective although OligoM‐coated RTNs show better transfection. Therefore, alginate coatings offer the potential for improved cationic nanoparticle airway delivery without PEGylation.
ISSN:2192-2640
2192-2659
2192-2659
DOI:10.1002/adhm.202400510