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However, their storage and transportation rely heavily on the cold chain to prevent rapid degradation in non\u2010frozen solutions, posing significant challenges for logistics and accessibility. Therefore, enhancing the in\u2010solution stability of mRNA LNPs is crucial. Herein, the role of helper phospholipids is investigated in storage stability of mRNA LNPs. By ratiometrically replacing the helper phospholipids (DSPC) with other alternative lipids (DOPS, DOTAP, and DOPE) in commercially available mRNA LNP formulation, enhanced in\u2010solution stability was observed with cationic lipid (DOTAP) substitution at 42 \u00b0C, room temperature (22 \u00b0C), and 4 \u00b0C. Further correlation of stability with microstructure analysis using cryogenic electron microscopy revealed that partial replacement with DOTAP enhances structural stability by promoting the formation of intact LNPs and reducing the occurrence of \u201cbleb\u201d\u2010like structures. Overall, the study provides insights into the structure\u2010stability relationship in mRNA LNPs, and offers new strategies to address the storage limitations of mRNA\u2010LNP products in the future.<\/jats:p>","DOI":"10.1002\/advs.202511637","type":"journal-article","created":{"date-parts":[[2025,10,30]],"date-time":"2025-10-30T09:50:46Z","timestamp":1761817846000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Replacing Helper Lipids With Cationic Lipids Enhances mRNA Lipid Nanoparticles Stability in Solution"],"prefix":"10.1002","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4671-4538","authenticated-orcid":false,"given":"Rui","family":"Chen","sequence":"first","affiliation":[{"name":"School of Chemical Engineering The University of Adelaide  Adelaide South Australia 5000 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