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Concretely, the combination of gene therapy with chemotherapy could increase its therapeutic index due to a synergistic effect. In this context, bovine serum albumin (BSA)-coated temozolomide (TMZ)-peptide (WRAP5)\/p53 gene-based plasmid DNA complexes were developed to promote payload co-delivery. Methods: Design of experiments (DoE) was employed to unravel the BSA-coated TMZ-WRAP5\/p53 nanocomplexes with the highest potential by considering the nitrogen to phosphate groups ratio (N\/P), and the BSA concentration as inputs and the size, polydispersity index, surface charge and p53-based plasmid complexation capacity (CC) as DoE outputs. Results: The obtained quadratic models were statistically significant (p-value &lt; 0.05) with an adequate coefficient of determination, and the correspondent optimal points were successfully validated. The optimal complex formulation had N\/P of 1.03, a BSA concentration of 0.08%, a size of approximately 182 nm, a zeta potential of +9.8 mV, and a pDNA CC of 96.5%. The optimal nanocomplexes are approximately spherical. A cytotoxicity assay showed that these BSA-coated TMZ-WRAP5\/p53 complexes did not elicit toxicity in normal brain cells, and a hemolysis study demonstrated the hemocompatibility of the complexes. The complexes were stable in cell culture medium and fetal bovine serum and assured pDNA protection and release. Moreover, the optimal BSA-coated complexes were able of gene transcription and promoted a significant inhibition of glioblastoma cell viability. Conclusions: The reported findings instigate the development of future research to evaluate their potential utility to TMZ\/p53 co-delivery. The DoE tool proved to be a powerful approach to explore and tailor the composition of BSA-coated TMZ-WRAP5\/p53 complexes, which are expected to contribute to the progress toward a more efficient therapy against cancer and, more specifically, against glioblastoma.<\/jats:p>","DOI":"10.3390\/pharmaceutics16111389","type":"journal-article","created":{"date-parts":[[2024,10,29]],"date-time":"2024-10-29T04:51:33Z","timestamp":1730177493000},"page":"1389","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Design of Experiments to Tailor the Potential of BSA-Coated Peptide Nanocomplexes for Temozolomide\/p53 Gene Co-Delivery"],"prefix":"10.3390","volume":"16","author":[{"given":"In\u00eas","family":"Afonso","sequence":"first","affiliation":[{"name":"CICS-UBI\u2014Health Sciences Research Centre, University of Beira Interior, 6200-506 Covilh\u00e3, Portugal"}]},{"given":"Ana R.","family":"Neves","sequence":"additional","affiliation":[{"name":"CICS-UBI\u2014Health Sciences Research Centre, University of Beira Interior, 6200-506 Covilh\u00e3, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3292-2184","authenticated-orcid":false,"given":"Dalinda","family":"Eus\u00e9bio","sequence":"additional","affiliation":[{"name":"CICS-UBI\u2014Health Sciences Research Centre, University of Beira Interior, 6200-506 Covilh\u00e3, Portugal"}]},{"given":"T\u00e2nia","family":"Albuquerque","sequence":"additional","affiliation":[{"name":"CICS-UBI\u2014Health Sciences Research Centre, University of Beira Interior, 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\/0000-0002-1224-9191","authenticated-orcid":false,"given":"Adriana O.","family":"Santos","sequence":"additional","affiliation":[{"name":"CICS-UBI\u2014Health Sciences Research Centre, University of Beira Interior, 6200-506 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, University of Beira Interior, 6200-506 Covilh\u00e3, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5049-4518","authenticated-orcid":false,"given":"Diana","family":"Costa","sequence":"additional","affiliation":[{"name":"CICS-UBI\u2014Health Sciences Research Centre, University of Beira Interior, 6200-506 Covilh\u00e3, Portugal"}]}],"member":"1968","published-online":{"date-parts":[[2024,10,29]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"71","DOI":"10.2147\/OTT.S366371","article-title":"Recurrent Glioblastoma: Ongoing Clinical Challenges and Future Prospects","volume":"16","author":"Pineda","year":"2023","journal-title":"OncoTargets Ther."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Vaz-Salgado, M.A., Villamayor, M., Albarr\u00e1n, V., Al\u00eda, V., Sotoca, P., Chamorro, J., Rosero, D., Barrill, A.M., Mart\u00edn, M., and Fernandez, E. 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