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While trehalose is a promising biocompatible cryoprotectant, its efficient intracellular delivery into non\u2010endocytic RBCs remains a major hurdle. Here, a lyophilized, ionizable lipid nanoparticle (LNP) platform is reported that overcomes this challenge via an acidic pH\u2010triggered membrane fusion mechanism. This approach, inspired by mRNA vaccine technology, enables rapid (&lt;30\u00a0min) and efficient intracellular delivery of trehalose. Systematic optimization of the LNP composition and process parameters resulted in a remarkable post\u2010thaw RBC recovery rate of 85%, an efficacy comparable to the clinical glycerol standard but achieved with a simple, single\u2010wash protocol. The efficacy depends on the specific lipid synergy to enable pH\u2010responsive fusion. Critically, the lyophilized LNP powder retains full functionality, ensuring long\u2010term stability and simplifying storage and transportation logistics. This study establishes a clinically relevant, translation\u2010ready cryopreservation strategy that bridges nanotechnology and transfusion medicine, offering a next\u2010generation solution to longstanding challenges in cell preservation.<\/jats:p>","DOI":"10.1002\/adhm.202502455","type":"journal-article","created":{"date-parts":[[2025,9,3]],"date-time":"2025-09-03T11:36:21Z","timestamp":1756899381000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Acidic pH\u2010Triggered Membrane Fusion Enables Lyophilized Lipid Nanoparticles as Potent Cryoprotectants for Human Erythrocytes"],"prefix":"10.1002","volume":"14","author":[{"given":"Xiangyang","family":"Li","sequence":"first","affiliation":[{"name":"Songshan Lake Materials Laboratory  Dongguan Guangdong 523808 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yushuang","family":"Wei","sequence":"additional","affiliation":[{"name":"Songshan Lake Materials Laboratory  Dongguan Guangdong 523808 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenwen","family":"Li","sequence":"additional","affiliation":[{"name":"Songshan Lake Materials Laboratory  Dongguan Guangdong 523808 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rong","family":"Xu","sequence":"additional","affiliation":[{"name":"Songshan Lake Materials Laboratory  Dongguan Guangdong 523808 China"},{"name":"National Laboratory of Solid State Microstructures and Department of Physics Collaborative Innovation Center of Advanced Microstructures Nanjing University  Nanjing Jiangsu 210093 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cheng","family":"Xu","sequence":"additional","affiliation":[{"name":"Songshan Lake Materials Laboratory  Dongguan Guangdong 523808 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Beijing","family":"Luo","sequence":"additional","affiliation":[{"name":"The Tenth Affiliated Hospital of Southern Medical University (Dongguan People's Hospital)  Dongguan Guangdong 523058 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kai","family":"Yang","sequence":"additional","affiliation":[{"name":"Center for Soft Condensed Matter Physics and Interdisciplinary Research &amp; School of Physical Science and Technology Soochow University  Suzhou Jiangsu 215006 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8418-9274","authenticated-orcid":false,"given":"Bing","family":"Yuan","sequence":"additional","affiliation":[{"name":"Songshan Lake Materials Laboratory  Dongguan Guangdong 523808 China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,9,3]]},"reference":[{"key":"e_1_2_9_1_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.blre.2019.100593"},{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.transci.2010.05.009"},{"key":"e_1_2_9_3_1","first-page":"82","volume":"8","author":"D'Alessandro A.","year":"2010","journal-title":"Blood Transfus."},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tmrv.2004.11.004"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bcmd.2012.02.004"},{"key":"e_1_2_9_6_1","first-page":"353","volume":"17","author":"Lagerberg J. 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