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DNA nanostructures can be a promising NAs delivery vehicle. Nonetheless, the potential of DNA nanostructures for neuronal cell delivery of therapeutic NAs is unexplored. Here, tetrahedral DNA nanostructures (TDN) as siRNA delivery scaffolds to neuronal cells, exploring the influence of functionalization with two different reported neuronal targeting ligands: C4\u20103 RNA aptamer and Tet1 peptide are investigated. Nanostructures are characterized in vitro, as well as in silico using molecular dynamic simulations to better understand the overall TDN structural stability. Enhancement of neuronal cell uptake of TDN functionalized with the C4\u20103 Aptamer (TDN\u2010Apt), not only in neuronal cell lines but also in primary neuronal cell cultures is demonstrated. Additionally, TDN and TDN\u2010Apt nanostructures carrying siRNA are shown to promote silencing in a process aided by chloroquine\u2010induced endosomal disruption. This work presents a thorough workflow for the structural and functional characterization of the proposed TDN as a nano\u2010scaffold for neuronal delivery of therapeutic NAs and for targeting ligands evaluation, contributing to the future development of new neuronal drug delivery systems based on DNA nanostructures.<\/jats:p>","DOI":"10.1002\/smll.202309140","type":"journal-article","created":{"date-parts":[[2024,2,12]],"date-time":"2024-02-12T02:45:20Z","timestamp":1707705920000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Enhancing Neuronal Cell Uptake of Therapeutic Nucleic Acids with Tetrahedral DNA Nanostructures"],"prefix":"10.1002","volume":"20","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7650-1317","authenticated-orcid":false,"given":"Ana S. 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Prof. Egas Moniz Lisbon 1649\u2010028 Portugal"}]},{"given":"Jo\u00e3o","family":"Cortinhas","sequence":"additional","affiliation":[{"name":"i3S (Instituto de Investiga\u00e7\u00e3o e Inova\u00e7\u00e3o em Sa\u00fade) Universidade do Porto INEB (Instituto Nacional de Engenharia Biom\u00e9dica) Rua Alfredo Allen, 208 Porto 4200\u2010135 Portugal"}]},{"given":"Joana A.","family":"Vidal Silva","sequence":"additional","affiliation":[{"name":"i3S (Instituto de Investiga\u00e7\u00e3o e Inova\u00e7\u00e3o em Sa\u00fade) Universidade do Porto INEB (Instituto Nacional de Engenharia Biom\u00e9dica) Rua Alfredo Allen, 208 Porto 4200\u2010135 Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8086-3310","authenticated-orcid":false,"given":"Sofia D.","family":"Santos","sequence":"additional","affiliation":[{"name":"i3S (Instituto de Investiga\u00e7\u00e3o e Inova\u00e7\u00e3o em Sa\u00fade) Universidade do Porto INEB (Instituto Nacional de Engenharia Biom\u00e9dica) Rua Alfredo Allen, 208 Porto 4200\u2010135 Portugal"}]},{"given":"Nuno C.","family":"Santos","sequence":"additional","affiliation":[{"name":"Instituto de Medicina Molecular Faculdade de Medicina Universidade de Lisboa Av. 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