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These efforts focus mainly on the tolerability and transfectability of new ionizable lipids and RNAs, or modulating LNPs biodistribution with active targeting strategies. However, most formulations follow the well\u2010established lipid proportions used in clinically approved products. Nevertheless, investigating the effects of LNPs composition on their biodistribution can expand the toolbox for particle design, leading to improved delivery strategies. Herein, a new LNPs (30\u2010n\u2010LNPs) formulation with increasing amounts of phospholipids is investigated as a possible mRNA delivery system for treating Inflammatory Bowel Diseases. Compared to LNPs with benchmark composition (b\u2010LNPs), n\u2010LNPs containing 30% distearoylphosphatidylcholine (DSPC) are well tolerated following intravenous administration and display natural targeting toward the inflamed colon in dextran sodium sulfate (DSS)\u2010colitis bearing mice, while de\u2010targeting clearing organs such as the liver and spleen. Using interleukin\u201010\u2010encoding mRNA as therapeutic cargo, n\u2010LNPs demonstrated a reduction of pathological burden in colitis\u2010bearing mice. n\u2010LNPs represent a starting point to further investigate the influence of LNPs composition on systemic biodistribution, ultimately opening new therapeutic modalities in different pathologies.<\/jats:p>","DOI":"10.1002\/advs.202408744","type":"journal-article","created":{"date-parts":[[2024,11,25]],"date-time":"2024-11-25T09:38:53Z","timestamp":1732527533000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":20,"title":["Lipid Nanoparticles With Fine\u2010Tuned Composition Show Enhanced Colon Targeting as a Platform for mRNA Therapeutics"],"prefix":"10.1002","volume":"12","author":[{"given":"Riccardo","family":"Rampado","sequence":"first","affiliation":[{"name":"Laboratory of Precision Nanomedicine Shmunis School of Biomedicine and Cancer Research Tel Aviv University  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