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Thanks to targeted and more efficient physical or chemical delivery techniques and to the refinement of their structure, non-viral plasmid DNA are now under intensive consideration as pharmaceutical drugs. Plasmids traditionally carry an antibiotic resistance gene for providing the selection pressure necessary for maintenance in a bacterial host. Nearly a dozen different antibiotic-free gene vectors have now been developed and are currently assessed in preclinical assays and phase I\/II clinical trials. Their reduced size leads to increased transfection efficiency and prolonged transgene expression. In addition, associating non-viral gene vectors and DNA transposons, which mediate transgene integration into the host genome, circumvents plasmid dilution in dividing eukaryotic cells which generate a loss of the therapeutic gene. Combining these novel molecular tools allowed a significantly higher yield of genetically engineered T and Natural Killer cells for adoptive immunotherapies due to a reduced cytotoxicity and increased transposition rate. This review describes the main progresses accomplished for safer, more efficient and cost-effective gene and cell therapies using non-viral approaches and antibiotic-free gene vectors.<\/jats:p>","DOI":"10.3390\/genes15030261","type":"journal-article","created":{"date-parts":[[2024,2,20]],"date-time":"2024-02-20T04:04:14Z","timestamp":1708401854000},"page":"261","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Antibiotic-Free Gene Vectors: A 25-Year Journey to Clinical Trials"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9619-5700","authenticated-orcid":false,"given":"Corinne","family":"Marie","sequence":"first","affiliation":[{"name":"Universit\u00e9 Paris Cit\u00e9, CNRS, Inserm, UTCBS, 75006 Paris, France"},{"name":"Chimie ParisTech, Universit\u00e9 PSL, 75005 Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel","family":"Scherman","sequence":"additional","affiliation":[{"name":"Universit\u00e9 Paris Cit\u00e9, CNRS, Inserm, UTCBS, 75006 Paris, France"},{"name":"Fondation Maladies Rares, 75014 Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,2,20]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1126\/science.abj6987","article-title":"The Complete Sequence of a Human Genome","volume":"376","author":"Nurk","year":"2022","journal-title":"Science"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"eabl3533","DOI":"10.1126\/science.abl3533","article-title":"A Complete Reference Genome Improves Analysis of Human Genetic Variation","volume":"376","author":"Aganezov","year":"2022","journal-title":"Science"},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Hickey, G., Monlong, J., Ebler, J., Novak, A.M., Eizenga, J.M., Gao, Y., Abel, H.J., Antonacci-Fulton, L.L., Asri, M., and Baid, G. 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