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In this work, the loading of various nucleic acids into small EVs via their spontaneous hybridization with preloaded non\u2010lamellar liquid crystalline lipid nanoparticles (LCNPs), forming hybrid EVs (HEVs) is described. It is demonstrated that LCNPs undergo pH\u2010dependent structural transitions from inverse hexagonal (\n                    <jats:italic>\n                      H\n                      <jats:sub>II<\/jats:sub>\n                    <\/jats:italic>\n                    ) phases at pH 5 to more disordered non\u2010lamellar phases, possibly inverse micellar (\n                    <jats:italic>\n                      L\n                      <jats:sub>2<\/jats:sub>\n                    <\/jats:italic>\n                    ) or sponge (\n                    <jats:italic>\n                      L\n                      <jats:sub>3<\/jats:sub>\n                    <\/jats:italic>\n                    ) phases, at pH 7.4, which are particularly suitable for inducing a controlled hybridization process with EVs. State\u2010of\u2010the\u2010art single\u2010particle analysis techniques reveal that LCNPs interact with various EV subpopulations at physiological conditions and that \u224840% of HEVs are loaded with the genetic cargo. Importantly, this study demonstrates that EV membrane proteins remain accessible on HEV surfaces, with their intrinsic enzymatic activity unaffected after the hybridization process. Finally, HEVs show in vitro improved transfection efficiencies compared to unhybridized LCNPs. In summary, this versatile platform holds potential for loading various nucleic acid molecules into native EVs and may help developing EV\u2010based therapeutics.\n                  <\/jats:p>","DOI":"10.1002\/advs.202404860","type":"journal-article","created":{"date-parts":[[2024,12,31]],"date-time":"2024-12-31T22:44:16Z","timestamp":1735685056000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":24,"title":["Loading of Extracellular Vesicles with Nucleic Acids via Hybridization with Non\u2010Lamellar Liquid Crystalline Lipid Nanoparticles"],"prefix":"10.1002","volume":"12","author":[{"given":"Johannes","family":"Bader","sequence":"first","affiliation":[{"name":"Institute of Pharmaceutical Sciences Department of Chemistry and Applied Biosciences ETH Zurich  Zurich 8093 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