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Receptor\u2010Targeted Nanocomplexes (RTN), comprise mixtures of cationic lipids and bifunctional peptides with receptor\u2010targeting and nucleic acid packaging properties. The aim of this study is to improve the mucus\u2010penetrating 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\u2010coated 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.<\/jats:p>","DOI":"10.1002\/adhm.202400510","type":"journal-article","created":{"date-parts":[[2024,11,13]],"date-time":"2024-11-13T07:12:15Z","timestamp":1731481935000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Low Molecular Weight Alginate Oligosaccharides as Alternatives to PEG for Enhancement of the Diffusion of Cationic Nanoparticles Through Cystic Fibrosis Mucus"],"prefix":"10.1002","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1473-9757","authenticated-orcid":false,"given":"Ruhina","family":"Maeshima","sequence":"first","affiliation":[{"name":"Department of Genetics and Genomic Medicine UCL Great Ormond Street Institute of Child Health  London WC1N 1EH UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aristides D.","family":"Tagalakis","sequence":"additional","affiliation":[{"name":"Department of Genetics and Genomic Medicine UCL Great Ormond Street Institute of Child Health  London WC1N 1EH UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dafni","family":"Gyftaki\u2010Venieri","sequence":"additional","affiliation":[{"name":"Department of Genetics and Genomic Medicine UCL Great Ormond Street Institute of Child Health  London WC1N 1EH UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stuart A.","family":"Jones","sequence":"additional","affiliation":[{"name":"Institute of Pharmaceutical Science Faculty of Life Science and Medicine King's College London  15\u2010 Stamford Street London SE1 9NH UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Philip D.","family":"Rye","sequence":"additional","affiliation":[{"name":"AlgiPharma AS  Industriveien 33 Sandvika Akershus 1337 Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anne","family":"T\u00f8ndervik","sequence":"additional","affiliation":[{"name":"Department of Biotechnology and Nanomedicine SINTEF Industry  Strindvegen 4 Trondheim 7034 Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"O. 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