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Lipid nanoparticles (LNPs) are the most clinically established non-viral delivery platform, yet their successful development depends on a well-defined chemistry, manufacturing, and controls (CMC) strategy that links lipid chemotype and process parameters to critical quality attributes (CQAs) and, ultimately, clinical performance. This review examines translation-critical decisions in mRNA-LNP development, beginning with a comparison of ionizable and permanently cationic lipid chemotypes in terms of efficacy\u2013tolerability trade-offs, biodegradability, and immune activation. We then contrast LNPs with polymeric and hybrid carriers, with emphasis on characterization burden, scalability, and regulatory precedent. Manufacturing approaches, including microfluidic scale-out and impinging-jet scale-up, are further discussed in relation to their effects on CQAs, critical process parameter (CPP) sensitivity, comparability, and cost. Beyond formulation and processing, we highlight the need for orthogonal analytical characterization, physiological stability assessment in plasma or serum, and stability-indicating profiling of lipid impurities and mRNA\u2013lipid adducts. We also discuss AI\/ML-ready metadata standards and early comparability planning for scale-up and post-approval changes. Together, these considerations provide a practical CMC-oriented framework for aligning formulation design, manufacturing control, and clinical translation of mRNA-LNP products.<\/jats:p>","DOI":"10.1186\/s11671-026-04864-4","type":"journal-article","created":{"date-parts":[[2026,8,13]],"date-time":"2026-08-13T10:27:06Z","timestamp":1786616826000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Critical chemistry manufacturing and controls considerations for mRNA lipid nanoparticle translation"],"prefix":"10.1186","volume":"21","author":[{"given":"Lanbo","family":"Liu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hua","family":"Gao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinghui","family":"Ruan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenna","family":"Lu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tianzhu","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xun","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guo-Qiang","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yating","family":"Xiao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,8,13]]},"reference":[{"key":"4864_CR1","doi-asserted-by":"publisher","first-page":"576","DOI":"10.1038\/190576a0","volume":"190","author":"S Brenner","year":"1961","unstructured":"Brenner S, Jacob F, Meselson M. 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