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Targeted drug delivery therapies that selectively attack malignant cells while sparing healthy tissue are essential to minimize side effects and reduce drug dosages. The sodium\u2010potassium ATPase (Na\n                    <jats:sup>+<\/jats:sup>\n                    \/K\n                    <jats:sup>+<\/jats:sup>\n                    \u2010ATPase), particularly its catalytic \u03b1\u2010subunit, is overexpressed in A549 non\u2010small cell lung cancer (NSCLC) and has thus emerged as a potential therapeutic target. Cardiac glycosides (CGs), plant\u2010derived secondary metabolites, specifically bind and inhibit this enzyme providing target engagement. Coupling CGs to a biocompatible carrier provides a promising new approach for a targeted\u2010orientated drug carrier. Among these nanocarrier systems, cell\u2010derived extracellular vesicles (EVs) gained attention due to their biocompatibility, tumor\u2010targeting capability, and ability to encapsulate compounds. Here, we developed a target\u2010oriented nanocarrier system by linking 3\u03b2\u2010azido\u20103\u2010deoxydigitoxigenin (CA), a semi\u2010synthetic cardenolide derivative, to the surface of A549 cell\u2010derived EVs. The EVs were characterized for particle concentration, size and protein markers. Surface modification was achieved via alkyne modification and click chemistry. Successful conjugation was confirmed by inhibition of the Na\n                    <jats:sup>+<\/jats:sup>\n                    \/K\n                    <jats:sup>+<\/jats:sup>\n                    \u2010ATPase activity. Co\u2010localization of CA\u2010modified EVs with the Na\n                    <jats:sup>+<\/jats:sup>\n                    \/K\n                    <jats:sup>+<\/jats:sup>\n                    \u2010ATPase was verified by confocal microscopy. Doxorubicin\u2010loaded, CA\u2010modified EVs reduced A549 cell viability to 45% after 48 h, demonstrating its potential use as new drug nanocarrier system.\n                  <\/jats:p>","DOI":"10.1002\/smtd.202501505","type":"journal-article","created":{"date-parts":[[2026,1,14]],"date-time":"2026-01-14T09:08:18Z","timestamp":1768381698000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Cardenolide\u2010Engineered Extracellular Vesicles Augment Drug Uptake and Cytotoxicity in Non\u2010small Cell Lung Cancer Cells"],"prefix":"10.1002","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0009-0001-3362-3664","authenticated-orcid":false,"given":"Maja","family":"Dorfner","sequence":"first","affiliation":[{"name":"Pharmaceutical Biology Friedrich\u2010Alexander\u2010University Erlangen\u2010N\u00fcrnberg  Erlangen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anika","family":"Mifka","sequence":"additional","affiliation":[{"name":"Pharmaceutical Biology Friedrich\u2010Alexander\u2010University Erlangen\u2010N\u00fcrnberg  Erlangen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9939-6900","authenticated-orcid":false,"given":"Rodrigo Maia","family":"de P\u00e1dua","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Products Universidade Federal de Minas Gerais  Belo Horizonte Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1893-4317","authenticated-orcid":false,"given":"Izabella Tha\u00eds","family":"da Silva","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences Federal University Santa Catarina, Florianopolis  SC Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1243-3765","authenticated-orcid":false,"given":"Iara Zanella","family":"Guterres","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences Federal University Santa Catarina, Florianopolis  SC Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lorenzo","family":"Sana","sequence":"additional","affiliation":[{"name":"Pharmaceutical Biology Friedrich\u2010Alexander\u2010University Erlangen\u2010N\u00fcrnberg  Erlangen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6688-5126","authenticated-orcid":false,"given":"Gregor","family":"Fuhrmann","sequence":"additional","affiliation":[{"name":"Pharmaceutical Biology Friedrich\u2010Alexander\u2010University Erlangen\u2010N\u00fcrnberg  Erlangen Germany"},{"name":"FAU NeW Friedrich\u2010Alexander\u2010Universit\u00e4t Erlangen\u2010N\u00fcrnberg  Erlangen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9799-8804","authenticated-orcid":false,"given":"Jennifer","family":"Munkert","sequence":"additional","affiliation":[{"name":"Pharmaceutical Biology Friedrich\u2010Alexander\u2010University Erlangen\u2010N\u00fcrnberg  Erlangen Germany"},{"name":"FAU NeW Friedrich\u2010Alexander\u2010Universit\u00e4t Erlangen\u2010N\u00fcrnberg  Erlangen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,1,14]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.3322\/caac.21834"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejmech.2025.117535"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1111\/1440-1681.12385"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1007\/978-1-4614-4756-6_15"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.biochem.71.102201.141218"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.biochem.6b01243"},{"key":"e_1_2_10_8_1","volume":"13","author":"Nguyen P. 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