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However, the delivery of the catalysts to the target tissues in vivo remains an unsolved challenge. The combination of catalytic NPs with extracellular vesicles (EVs) has been proposed as a promising approach to improve the delivery of therapeutic nanomaterials to the desired organs. In this study, we have developed a nanoscale bio-hybrid vector using a CO-mediated reduction at low temperature to generate ultrathin catalytic Pd nanosheets (PdNSs) as catalysts directly inside cancer-derived EVs. We have also compared their biodistribution with that of PEGylated PdNSs delivered by the EPR effect. Our results indicate that the accumulation of PdNSs in the tumour tissue was significantly higher when they were administered within the EVs compared to the PEGylated PdNSs. Conversely, the amount of Pd found in non-target organs (i.e., liver) was lowered. Once the Pd-based catalytic EVs were accumulated in the tumours, they enabled the activation of a paclitaxel prodrug demonstrating their ability to carry out bio-orthogonal uncaging chemistries in vivo for cancer therapy.<\/jats:p>","DOI":"10.3390\/cells13080691","type":"journal-article","created":{"date-parts":[[2024,4,16]],"date-time":"2024-04-16T08:41:06Z","timestamp":1713256866000},"page":"691","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Extracellular Vesicles-Mediated Bio-Orthogonal Catalysis in Growing Tumors"],"prefix":"10.3390","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8762-5457","authenticated-orcid":false,"given":"Maria","family":"Sancho-Albero","sequence":"first","affiliation":[{"name":"Instituto de Investigaci\u00f3n Sanitaria de Arag\u00f3n (IIS Arag\u00f3n), Avda. San Juan Bosco, 13, 50009 Zaragoza, Spain"},{"name":"Instituto de Nanociencia y Materiales de Arag\u00f3n (INMA), CSIC-Universidad de Zaragoza, Campus Rio Ebro, Edificio I+D, C\/Poeta Mariano Esquillor, s\/n, 50018 Zaragoza, Spain"},{"name":"Networking Research Center in Biomaterials, Bioengineering and Nanomedicine (CIBERBBN), Instituto de Salud Carlos III, 28029 Madrid, Spain"},{"name":"Department of Chemical and Enviromental Engineering, University of Zaragoza, Campus Rio Ebro, C\/Mar\u00eda de Luna, 3, 50018 Zaragoza, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6873-5244","authenticated-orcid":false,"given":"Victor","family":"Sebastian","sequence":"additional","affiliation":[{"name":"Instituto de Investigaci\u00f3n Sanitaria de Arag\u00f3n (IIS Arag\u00f3n), Avda. 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San Juan Bosco, 13, 50009 Zaragoza, Spain"},{"name":"Networking Research Center in Biomaterials, Bioengineering and Nanomedicine (CIBERBBN), Instituto de Salud Carlos III, 28029 Madrid, Spain"},{"name":"Instituto de Salud Carlos III, 28222 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1029-2855","authenticated-orcid":false,"given":"Asier","family":"Unciti-Broceta","sequence":"additional","affiliation":[{"name":"Edinburgh Cancer Research, CRUK Scotland Centre, Institute of Genetics & Cancer, University of Edinburgh, Edinburgh EH4 2XR, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8701-9745","authenticated-orcid":false,"given":"Jesus","family":"Santamaria","sequence":"additional","affiliation":[{"name":"Instituto de Investigaci\u00f3n Sanitaria de Arag\u00f3n (IIS Arag\u00f3n), Avda. 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