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We designed novel pH\u2010switchable 3\u03b1\u2010amino lithocholate\u2010modified lipids (LMLs) with a unique mechanism of action. Under weakly basic conditions, the 3\u03b1\u2010amino lithocholate moieties sequester within LNP membranes, while acidic environments (e.g., endosomal pH 5.0) trigger their reorientation to the lipid\u2010water interface. The pH\u2010driven flipping behavior amplified the surface charge of LNPs, yielding a much higher zeta potential (+4\u20137 mV) than LNPs incorporating the 3\u03b1\u2010OH LMLs (0 mV) or the benchmark lipid Dlin\u2010MC3\u2010DMA (MC3) (\u22123 mV). In vitro studies found that 3\u03b1\u2010amino LMLs\u2010based LNPs had\u00a0endosomal escape efficiencies comparable to LNP\u2010MC3, whereas the 3\u03b1\u2010OH LML had no activity. In a mouse model, the lead compound, LML4 (pKa = 6.3), showed an efficacy equivalent to MC3, reducing serum Factor VII protein levels by approximately 40% following siRNA treatment at 0.5 mg\/kg. We propose that the dual advantages of 3\u03b1\u2010amino LMLs, including acidity\u2010induced charge amplification and membrane reorientation, synergize to promote endosomal membrane disruption. This dynamic flipping process could represent a revolutionary shift in lipid design for next\u2010generation LNPs with high pH\u2010reactivity, addressing the persistent challenge of inefficient intracellular RNA release.<\/jats:p>","DOI":"10.1002\/adhm.202504363","type":"journal-article","created":{"date-parts":[[2025,12,24]],"date-time":"2025-12-24T06:51:17Z","timestamp":1766559077000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Rational Design of pH\u2010Switchable 3\u03b1\u2010Amino Lithocholate\u2010Modified Lipids for Efficient siRNA Delivery"],"prefix":"10.1002","volume":"15","author":[{"given":"Xueying","family":"Gu","sequence":"first","affiliation":[{"name":"State Key Laboratory of Mechanism and Quality of Chinese Medicine Institute of Chinese Medical Sciences University of Macau  Macau P. R. 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