{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T19:13:03Z","timestamp":1788289983559,"version":"build-2803163510"},"reference-count":36,"publisher":"American Chemical Society (ACS)","issue":"8","license":[{"start":{"date-parts":[[2026,6,8]],"date-time":"2026-06-08T00:00:00Z","timestamp":1780876800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100012131","name":"Department of Science and Technology of Liaoning Province","doi-asserted-by":"publisher","award":["2023JH2\/101700343"],"award-info":[{"award-number":["2023JH2\/101700343"]}],"id":[{"id":"10.13039\/501100012131","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100018617","name":"Liaoning Revitalization Talents Program","doi-asserted-by":"publisher","award":["XLYC2202039"],"award-info":[{"award-number":["XLYC2202039"]}],"id":[{"id":"10.13039\/501100018617","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/na","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["21991103"],"award-info":[{"award-number":["21991103"]}],"id":[{"id":"10.13039\/na","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/na","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["22178336"],"award-info":[{"award-number":["22178336"]}],"id":[{"id":"10.13039\/na","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/na","name":"Dalian Institute of Chemical Physics","doi-asserted-by":"publisher","award":["DICP I202216"],"award-info":[{"award-number":["DICP I202216"]}],"id":[{"id":"10.13039\/na","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/na","name":"Dalian Institute of Chemical Physics","doi-asserted-by":"publisher","award":["Y161220903"],"award-info":[{"award-number":["Y161220903"]}],"id":[{"id":"10.13039\/na","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,8,27]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Controlling the internal architecture and morphology of lipid nanoparticles (LNPs) beyond their size remains a central challenge in nanoparticle engineering. Conventional micromixer-based assembly methods provide rapid mixing but lack the temporal resolution to manipulate the multiple competing kinetic processes that occur during LNP self-assembly. Here, we demonstrate kinetically controlled fabrication of Janus-structured surface nanobubble\u2013lipid nanoparticles (SNB-LNPs) using an ultrasonic micromixer that enables independent tuning of three critical time scales: mixing time (tm), bubble generation time (tb), and LNP self-assembly time (ta). By systematically mapping these time scales, we establish an assembly kinetic zone diagram that defines the process windows for distinct nanoparticle architectures, including spherical LNPs, bleb LNPs, and the previously inaccessible SNB-LNPs. Cryogenic transmission electron microscopy and small-angle neutron scattering confirm the Janus morphology of SNB-LNPs, featuring a gas-filled nanobubble compartment (\u223c17 vol % gas phase) attached to a lipid\u2013mRNA core. The assembly outcome can be further modulated by gas supersaturation and lipid shell composition, providing additional degrees of freedom for structural control. As a proof of concept, the ultrasound-responsive SNB-LNPs demonstrate enhanced mRNA delivery both in vitro and in vivo. This work establishes a process engineering framework for fabricating multicompartment nanoparticles with nonequilibrium architectures through kinetic control in continuous-flow microreactors.<\/jats:p>","DOI":"10.1021\/cbe.6c00022","type":"journal-article","created":{"date-parts":[[2026,6,8]],"date-time":"2026-06-08T07:11:46Z","timestamp":1780902706000},"page":"713-722","source":"Crossref","is-referenced-by-count":0,"title":["Kinetically Controlled\nAssembly of Janus-Structured\nNanobubble\u2013Lipid Nanoparticles via Ultrasonic Micromixing"],"prefix":"10.1021","volume":"3","author":[{"given":"Zhikai","family":"Liu","sequence":"first","affiliation":[{"name":"Chinese Academy of Sciences , , ,","place":["Dalian, China, 116023"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yufeng","family":"Zhang","sequence":"additional","affiliation":[{"name":"Dalian University of Technology , , ,","place":["Dalian, China, 116024"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daixin","family":"Chen","sequence":"additional","affiliation":[{"name":"Chinese Academy of Sciences , , ,","place":["Dalian, China, 116023"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9828-4755","authenticated-orcid":true,"given":"Mei","family":"Yang","sequence":"additional","affiliation":[{"name":"Chinese Academy of Sciences , , ,","place":["Dalian, China, 116023"]},{"name":"University of Chinese Academy of Sciences , ,","place":["Beijing, China, 101408"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1382-9195","authenticated-orcid":true,"given":"Liming","family":"Wang","sequence":"additional","affiliation":[{"name":"Chinese Academy of Sciences , , ,","place":["Beijing, China, 100049"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hanqiu","family":"Jiang","sequence":"additional","affiliation":[{"name":"Chinese Academy of Sciences , , ,","place":["Beijing, China, 100049"]},{"name":"Spallation Neutron Source Science Center , ,","place":["Dongguan, China, 523803"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7913-986X","authenticated-orcid":true,"given":"Shubo","family":"Du","sequence":"additional","affiliation":[{"name":"Dalian University of Technology , , ,","place":["Dalian, China, 116024"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7015-8992","authenticated-orcid":true,"given":"Jiaqi","family":"Lin","sequence":"additional","affiliation":[{"name":"Dalian University of Technology , , ,","place":["Dalian, China, 116024"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5290-7921","authenticated-orcid":true,"given":"Guangwen","family":"Chen","sequence":"additional","affiliation":[{"name":"Chinese Academy of Sciences , , ,","place":["Dalian, China, 116023"]},{"name":"University of Chinese Academy of Sciences , ,","place":["Beijing, China, 101408"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,6,8]]},"reference":[{"key":"2026090114183132600_cit1","doi-asserted-by":"publisher","DOI":"10.1038\/mtna.2012.28","article-title":"Microfluidic Synthesis\nof Highly Potent Limit-Size Lipid Nanoparticles for In Vivo Delivery\nof siRNA","volume":"1","author":"Belliveau","year":"2012","journal-title":"Mol. Ther. Nucleic Acids"},{"issue":"12","key":"2026090114183132600_cit2","doi-asserted-by":"publisher","first-page":"1078","DOI":"10.1038\/s41578-021-00358-0","article-title":"Lipid Nanoparticles\nfor mRNA Delivery","volume":"6","author":"Hou","year":"2021","journal-title":"Nat. Rev. Mater."},{"issue":"11","key":"2026090114183132600_cit3","doi-asserted-by":"publisher","first-page":"817","DOI":"10.1038\/s41573-021-00283-5","article-title":"mRNA Vaccines for Infectious Diseases:\nPrinciples, Delivery and Clinical Translation","volume":"20","author":"Chaudhary","year":"2021","journal-title":"Nat. Rev. Drug Discovery"},{"issue":"4","key":"2026090114183132600_cit4","doi-asserted-by":"publisher","first-page":"261","DOI":"10.1038\/nrd.2017.243","article-title":"mRNA Vaccines \u2500\nA New Era in Vaccinology","volume":"17","author":"Pardi","year":"2018","journal-title":"Nat. Rev. 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Mater."},{"issue":"1","key":"2026090114183132600_cit11","doi-asserted-by":"publisher","first-page":"2","DOI":"10.1021\/acs.accounts.1c00544","article-title":"Chemistry of Lipid\nNanoparticles for RNA Delivery","volume":"55","author":"Eygeris","year":"2022","journal-title":"Acc. Chem. Res."},{"issue":"5","key":"2026090114183132600_cit12","doi-asserted-by":"publisher","first-page":"701","DOI":"10.1038\/s41563-020-00886-0","article-title":"Membrane-Destabilizing\nIonizable\nPhospholipids for Organ-Selective mRNA Delivery and CRISPR\u2013Cas\nGene Editing","volume":"20","author":"Liu","year":"2021","journal-title":"Nat. Mater."},{"issue":"2","key":"2026090114183132600_cit13","doi-asserted-by":"publisher","first-page":"172","DOI":"10.1038\/nbt.1602","article-title":"Rational\nDesign of Cationic Lipids for siRNA Delivery","volume":"28","author":"Semple","year":"2010","journal-title":"Nat. Biotechnol."},{"key":"2026090114183132600_cit14","doi-asserted-by":"publisher","DOI":"10.1016\/j.cej.2025.159318","article-title":"Controlled\nPreparation of Lipid Nanoparticles in Microreactors: Mixing Time,\nMorphology and mRNA Delivery","volume":"505","author":"Chen","year":"2025","journal-title":"Chem. Eng. J."},{"issue":"38","key":"2026090114183132600_cit15","doi-asserted-by":"publisher","first-page":"33991","DOI":"10.1021\/acsnano.5c09800","article-title":"Manufacturing mRNA-Loaded\nLipid Nanoparticles with Precise Size and Morphology Control","volume":"19","author":"Devos","year":"2025","journal-title":"ACS Nano"},{"key":"2026090114183132600_cit16","doi-asserted-by":"publisher","DOI":"10.1016\/j.ces.2024.119846","article-title":"Continuous\nSynthesis of Monodisperse Polymer Nanoparticles: New Insights into\nthe Effects of Experimental Variables under Controlled Mixing Conditions","volume":"288","author":"Yao","year":"2024","journal-title":"Chem. Eng. 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Rep."},{"issue":"4","key":"2026090114183132600_cit25","doi-asserted-by":"publisher","first-page":"6709","DOI":"10.1021\/acsnano.0c10064","article-title":"Apolipoprotein E Binding\nDrives Structural and Compositional\nRearrangement of mRNA-Containing Lipid Nanoparticles","volume":"15","author":"Sebastiani","year":"2021","journal-title":"ACS Nano"},{"key":"2026090114183132600_cit26","doi-asserted-by":"publisher","first-page":"369","DOI":"10.1016\/j.omtn.2021.03.008","article-title":"Functionalized Lipid Nanoparticles\nfor Subcutaneous\nAdministration of mRNA to Achieve Systemic Exposures of a Therapeutic\nProtein","volume":"24","author":"Davies","year":"2021","journal-title":"Mol. Ther. Nucleic Acids"},{"issue":"18","key":"2026090114183132600_cit27","doi-asserted-by":"publisher","first-page":"9023","DOI":"10.1039\/C9NR02004G","article-title":"Fusion-Dependent\nFormation of Lipid Nanoparticles Containing Macromolecular Payloads","volume":"11","author":"Kulkarni","year":"2019","journal-title":"Nanoscale"},{"issue":"7","key":"2026090114183132600_cit28","doi-asserted-by":"publisher","first-page":"638","DOI":"10.1038\/nbt.2612","article-title":"Image-Based Analysis\nof Lipid Nanoparticle\u2013Mediated siRNA Delivery, Intracellular\nTrafficking and Endosomal Escape","volume":"31","author":"Gilleron","year":"2013","journal-title":"Nat. Biotechnol."},{"issue":"11","key":"2026090114183132600_cit29","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2307800120","article-title":"Endosomal Escape: A Bottleneck for\nLNP-Mediated Therapeutics","volume":"121","author":"Chatterjee","year":"2024","journal-title":"Proc. Natl. Acad.\nSci. U.S.A."},{"issue":"11","key":"2026090114183132600_cit30","doi-asserted-by":"publisher","first-page":"10481","DOI":"10.1021\/acsami.8b21398","article-title":"Lipid-mRNA Nanoparticle\nDesigned to Enhance Intracellular Delivery Mediated by Shock Waves","volume":"11","author":"Zhang","year":"2019","journal-title":"ACS Appl. Mater. Interfaces"},{"issue":"14","key":"2026090114183132600_cit31","doi-asserted-by":"publisher","first-page":"2766","DOI":"10.1016\/j.bpj.2021.03.012","article-title":"Encapsulation State\nof Messenger RNA Inside Lipid Nanoparticles","volume":"120","author":"Brader","year":"2021","journal-title":"Biophys. J."},{"issue":"4","key":"2026090114183132600_cit32","doi-asserted-by":"publisher","first-page":"313","DOI":"10.1038\/s41565-020-0669-6","article-title":"Selective\nOrgan Targeting (SORT) Nanoparticles for Tissue-Specific mRNA Delivery\nand CRISPR\u2013Cas Gene Editing","volume":"15","author":"Cheng","year":"2020","journal-title":"Nat. Nanotechnol."},{"issue":"37","key":"2026090114183132600_cit33","doi-asserted-by":"publisher","first-page":"33387","DOI":"10.1021\/acsnano.5c09956","article-title":"A Machine\nLearning Assisted Tool\nand Numerical Model for Analyzing Lipid Nanoparticles Based on Cryogenic\nTransmission Electron Microscopy Images","volume":"19","author":"Ip","year":"2025","journal-title":"ACS\nNano"},{"issue":"2","key":"2026090114183132600_cit34","doi-asserted-by":"publisher","DOI":"10.1016\/j.omtm.2025.101578","article-title":"Morphological changes induced by\nbuffer exchange during preparation of mRNA-lipid nanoparticles occur\nin a stepwise manner as pH is elevated","volume":"33","author":"He","year":"2025","journal-title":"Mol.\nTher. Methods Clin. Dev."},{"key":"2026090114183132600_cit35","doi-asserted-by":"publisher","DOI":"10.1016\/j.jconrel.2025.114082","article-title":"Structural\nCharacterization of mRNA Lipid Nanoparticles (LNPs) in the Presence\nof mRNA-Free LNPs","volume":"386","author":"Chen","year":"2025","journal-title":"J. Controlled Release"},{"issue":"1","key":"2026090114183132600_cit36","doi-asserted-by":"publisher","first-page":"4135","DOI":"10.1038\/s41467-025-58523-w","article-title":"Liposomal Lipid Nanoparticles for\nExtrahepatic Delivery of mRNA","volume":"16","author":"Cheng","year":"2025","journal-title":"Nat. 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