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However, their predominant accumulation in liver after systemic administration and inefficient endosomal escape remain key bottlenecks for productive cytosolic delivery and gene expression. Here, we introduce a synthetic ionizable lipid with a dual pKa property that is retained in formulated LNPs. We show that after intravenous injection, these dual pKa LNPs produce lung\u2010selective mRNA expression with higher potency than a cationic lipid\u2010rich comparator while remaining well tolerated. Using molecular dynamics simulations, we find that protonation state can support two distinct interaction modes between the ionizable lipid and endosomal membranes, suggesting a mechanistic basis for efficient endosomal escape. Moreover, the formulation maintains robust pulmonary expression and delivers therapeutic benefit in an acute lung inflammation model. These results establish a structure\u2010property relationship within the ionizable lipid\u2010based LNPs investigated here and identify dual apparent pKa behavior as a promising feature for potent and tolerable lung\u2010targeted RNA delivery.<\/jats:p>","DOI":"10.1002\/advs.77387","type":"journal-article","created":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T14:07:06Z","timestamp":1788962826000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Dual pKa Lipid Nanoparticles for Lung\u2010tropic mRNA Delivery and pH\u2010Programmed Endosomal Escape"],"prefix":"10.1002","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2318-4602","authenticated-orcid":false,"given":"Seong Gi","family":"Lim","sequence":"first","affiliation":[{"name":"Department of Medical Life Sciences and Department of Medical Sciences (Graduate School) College of Medicine The Catholic University of Korea  Seoul Republic of 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