{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T09:06:59Z","timestamp":1790672819369,"version":"4.1.0"},"reference-count":77,"publisher":"MDPI AG","issue":"19","license":[{"start":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T00:00:00Z","timestamp":1790640000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100007045","name":"Secretar\u00eda de Ciencia, Humanidades, Tecnolog\u00eda e Innovaci\u00f3n","doi-asserted-by":"publisher","award":["CBF-2025-I-3401"],"award-info":[{"award-number":["CBF-2025-I-3401"]}],"id":[{"id":"10.13039\/501100007045","id-type":"DOI","asserted-by":"publisher"}]},{"award":["CBF-2025-I-3401"],"award-info":[{"award-number":["CBF-2025-I-3401"]}],"id":[{"id":"https:\/\/ror.org\/059ex5q34","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Nanomaterials"],"abstract":"<jats:p>DNA has evolved from a carrier of genetic information into a programmable material for constructing nanoscale architectures with precise structural and functional control. Among these systems, tetrahedral DNA nanostructures (TDNs) comprise at least two experimentally distinct structural families: small scaffold-free tetrahedra assembled from a few synthetic oligonucleotides, often termed tetrahedral framework nucleic acids (tFNAs), and larger scaffolded or wireframe tetrahedral DNA-origami objects. This review integrates assembly principles, computational and sequence-level design, physicochemical stability, fabrication, structural validation, biological performance, and translational evidence while keeping these two families analytically separate. For few-strand TDNs, particular attention is given to ionic conditions, pH, temperature, serum and nuclease exposure, cellular uptake, targeting aptamers, and delivery of drugs and regulatory nucleic acids; scaffolded tetrahedral origami is discussed where its routing, mechanics, manufacturing, or larger spatial capacity are directly relevant. Recent in vivo studies provide evidence for tissue distribution, transdermal delivery, and short-term biocompatibility of selected few-strand TDN formulations, but the translational evidence remains predominantly preclinical. Rather than positioning TDNs as universally superior nanocarriers, this review emphasizes architecture-specific evidence, quantitative experimental conditions, and the limits of transferring conclusions between structural families. Progress toward translational nanomedicine will require validated design rules, matched-condition benchmarking, pharmacokinetic and biodistribution studies, scalable manufacturing, standardized quality attributes, and rigorous safety assessment.<\/jats:p>","DOI":"10.3390\/nano16191227","type":"journal-article","created":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T08:12:42Z","timestamp":1790669562000},"page":"1227","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Tetrahedral DNA Nanostructures: A Structural-Family-Aware Review from Computational Design and Biological Stability to Translational Nanomedicine"],"prefix":"10.3390","volume":"16","author":[{"given":"Paulina G.","family":"Rosales-P\u00e9rez","sequence":"first","affiliation":[{"name":"University Center for Biological and Agricultural Sciences (CUCBA), Universidad de Guadalajara, Guadalajara 45200, Mexico"},{"name":"Industrial Biotechnology Unit, Center for Research and Assistance in Technology and Design of the State of Jalisco, A.C. (CIATEJ), Zapopan 44270, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8088-9724","authenticated-orcid":false,"given":"J. Alejandro","family":"Morales","sequence":"additional","affiliation":[{"name":"Biodigital Innovation Lab, Translational Bioengineering Department, Centro Universitario de Ciencias Exactas e Ingenier\u00edas (CUCEI), Universidad de Guadalajara, Guadalajara 44430, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7283-8035","authenticated-orcid":false,"given":"Luis J.","family":"Figueroa-Y\u00e1\u00f1ez","sequence":"additional","affiliation":[{"name":"Industrial Biotechnology Unit, Center for Research and Assistance in Technology and Design of the State of Jalisco, A.C. (CIATEJ), Zapopan 44270, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,9,29]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"297","DOI":"10.1038\/nature04586","article-title":"Folding DNA to create nanoscale shapes and patterns","volume":"440","author":"Rothemund","year":"2006","journal-title":"Nature"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"725","DOI":"10.1126\/science.1174251","article-title":"Folding DNA into twisted and curved nanoscale shapes","volume":"325","author":"Dietz","year":"2009","journal-title":"Science"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"414","DOI":"10.1038\/nature08016","article-title":"Self-assembly of DNA into nanoscale three-dimensional shapes","volume":"459","author":"Douglas","year":"2009","journal-title":"Nature"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"5001","DOI":"10.1093\/nar\/gkp436","article-title":"Rapid prototyping of 3D DNA-origami shapes with caDNAno","volume":"37","author":"Douglas","year":"2009","journal-title":"Nucleic Acids Res."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"264","DOI":"10.1002\/anie.201005911","article-title":"Crystalline two-dimensional DNA-origami arrays","volume":"50","author":"Liu","year":"2011","journal-title":"Angew. 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