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variety of human cancers, glioblastoma remains the most lethal brain tumor. In recent years, cancer gene therapy focused on non-viral vectors which emerged as a promising approach to glioblastoma treatment. Transferrin (Tf) easily penetrates brain cells of the blood\u2013brain barrier, and its receptor is highly expressed in this barrier and glioblastoma cells. Therefore, the development of delivery systems containing Tf appears as a reliable strategy to improve their brain cells targeting ability and cellular uptake. In this work, a cell-penetrating peptide (WRAP5), bearing a Tf-targeting sequence, has been exploited to condense tumor suppressor p53-encoding plasmid DNA (pDNA) for the development of nanocomplexes. To increase the functionality of developed nanocomplexes, the drug Temozolomide (TMZ) was also incorporated into the formulations. The physicochemical properties of peptide\/pDNA complexes were revealed to be dependent on the nitrogen to phosphate groups ratio and can be optimized to promote efficient cellular internalization. A confocal microscopy study showed the capacity of developed complexes for efficient glioblastoma cell transfection and consequent pDNA delivery into the nucleus, where efficient gene expression took place, followed by p53 protein production. Of promise, these peptide\/pDNA complexes induced a significant decrease in the viability of glioblastoma cells. The set of data reported significantly support further in vitro research to evaluate the therapeutic potential of developed complexes against glioblastoma.<\/jats:p>","DOI":"10.3390\/pharmaceutics14102213","type":"journal-article","created":{"date-parts":[[2022,10,19]],"date-time":"2022-10-19T00:58:51Z","timestamp":1666141131000},"page":"2213","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Development of WRAP5 Peptide Complexes for Targeted Drug\/Gene Co-Delivery toward Glioblastoma Therapy"],"prefix":"10.3390","volume":"14","author":[{"given":"Ana Raquel","family":"Neves","sequence":"first","affiliation":[{"name":"CICS-UBI\u2014Health Sciences Research Centre, Universidade da Beira Interior, Avenida Infante D. 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Henrique, 6200-506 Covilh\u00e3, Portugal"},{"name":"UCIBIO\u2014Applied Molecular Biosciences Unit, Departamento de Qu\u00edmica, Faculdade de Ci\u00eancias e Tecnologia, Universidade NOVA de Lisboa, 2829-516 Caparica, Portugal"},{"name":"Associate Laboratory i4HB\u2014Institute for Health and Bioeconomy, NOVA School of Science and Technology, Universidade NOVA de Lisboa, 2819-516 Caparica, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6074-7825","authenticated-orcid":false,"given":"Cec\u00edlia","family":"Santos","sequence":"additional","affiliation":[{"name":"CICS-UBI\u2014Health Sciences Research Centre, Universidade da Beira Interior, Avenida Infante D. Henrique, 6200-506 Covilh\u00e3, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5391-9641","authenticated-orcid":false,"given":"Eric","family":"Viv\u00e8s","sequence":"additional","affiliation":[{"name":"PhyMedExp, Universit\u00e9 de Montpellier, INSERM, CNRS, 34295 Montpellier, France"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6955-1340","authenticated-orcid":false,"given":"Prisca","family":"Boisgu\u00e9rin","sequence":"additional","affiliation":[{"name":"PhyMedExp, Universit\u00e9 de Montpellier, INSERM, CNRS, 34295 Montpellier, France"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6910-7576","authenticated-orcid":false,"given":"Lu\u00eds A.","family":"Passarinha","sequence":"additional","affiliation":[{"name":"CICS-UBI\u2014Health Sciences Research Centre, Universidade da Beira Interior, Avenida Infante D. Henrique, 6200-506 Covilh\u00e3, Portugal"},{"name":"UCIBIO\u2014Applied Molecular Biosciences Unit, Departamento de Qu\u00edmica, Faculdade de Ci\u00eancias e Tecnologia, Universidade NOVA de Lisboa, 2829-516 Caparica, Portugal"},{"name":"Associate Laboratory i4HB\u2014Institute for Health and Bioeconomy, NOVA School of Science and Technology, Universidade NOVA de Lisboa, 2819-516 Caparica, Portugal"},{"name":"Laborat\u00f3rio de F\u00e1rmaco-Toxicologia\u2014UBIMedical, Universidade da Beira Interior, 6200-001 Covilh\u00e3, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9155-7581","authenticated-orcid":false,"given":"\u00c2ngela","family":"Sousa","sequence":"additional","affiliation":[{"name":"CICS-UBI\u2014Health Sciences Research Centre, Universidade da Beira Interior, Avenida Infante D. Henrique, 6200-506 Covilh\u00e3, Portugal"}]},{"given":"Diana","family":"Costa","sequence":"additional","affiliation":[{"name":"CICS-UBI\u2014Health Sciences Research Centre, Universidade da Beira Interior, Avenida Infante D. Henrique, 6200-506 Covilh\u00e3, Portugal"}]}],"member":"1968","published-online":{"date-parts":[[2022,10,18]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"102585","DOI":"10.1016\/j.pdpdt.2021.102585","article-title":"Targeting glioblastoma stem cells: The first step of photodynamic therapy","volume":"36","author":"Vilchez","year":"2021","journal-title":"Photodiagn. Photodyn. Ther."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"173055","DOI":"10.1016\/j.ejphar.2020.173055","article-title":"The effects of cannabinoids on glioblastoma growth: A systematic review with meta-analysis of animal model studies","volume":"876","author":"Marcelino","year":"2020","journal-title":"Eur. J. 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