{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,3]],"date-time":"2026-03-03T01:35:56Z","timestamp":1772501756522,"version":"3.50.1"},"reference-count":58,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2025,12,23]],"date-time":"2025-12-23T00:00:00Z","timestamp":1766448000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Portuguese Foundation for Science and Technology (FCT)\/MCTES","award":["UIDB\/00709\/2020"],"award-info":[{"award-number":["UIDB\/00709\/2020"]}]},{"name":"Portuguese Foundation for Science and Technology (FCT)\/MCTES","award":["UIDP\/00709\/2020"],"award-info":[{"award-number":["UIDP\/00709\/2020"]}]},{"name":"Portuguese Foundation for Science and Technology (FCT)\/MCTES","award":["2023.00136.RESTART"],"award-info":[{"award-number":["2023.00136.RESTART"]}]},{"name":"DryVac project","award":["2023.00136.RESTART"],"award-info":[{"award-number":["2023.00136.RESTART"]}]},{"name":"FCT","award":["2020.10201.BD"],"award-info":[{"award-number":["2020.10201.BD"]}]},{"name":"FCT","award":["CEECINST\/00016\/2021\/CP2828\/CT0003"],"award-info":[{"award-number":["CEECINST\/00016\/2021\/CP2828\/CT0003"]}]},{"DOI":"10.13039\/501100001411","name":"Indian Council of Medical Research, Government of India","doi-asserted-by":"crossref","award":["2021-8945"],"award-info":[{"award-number":["2021-8945"]}],"id":[{"id":"10.13039\/501100001411","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Vaccines"],"abstract":"<jats:p>Background\/Objectives: Cervical cancer is a leading cause of cancer-related mortality among women, primarily driven by persistent infections with high-risk human papillomavirus (HPV), particularly HPV-16. Vaccines based on plasmid DNA encoding the viral oncogenes E6 and E7 represent a promising immunotherapeutic strategy, but their efficacy remains limited due to poor cellular uptake. Cell-penetrating peptides such as RALA improve intracellular delivery, and functionalization with octa-arginine peptide conjugated to mannose (R8M) further enhances targeting of antigen-presenting cells (APCs). This study aimed to obtain the minicircle DNA (mcDNA) encoding mutant HPV-16 E6 and\/or E7 antigens, and optimize its complexation with mannosylated RALA-based nanoparticles to improve vector delivery and consequently antigen presentation. Methods: Nanoparticles were formulated at different concentrations of RALA, with and without R8M functionalization. Their characterization included hydrodynamic diameter, polydispersity index, zeta potential, complexation efficiency (CE), stability, morphology, and Fourier-Transform Infrared Spectroscopy. In vitro assays in JAWS II dendritic cells (DCs) assessed biocompatibility, transfection efficiency and target gene expression. Results: Optimal conditions were obtained at 72.5 \u00b5g\/mL of RALA, producing nanoparticles smaller than 150 nm with high CE (&gt;97%) and uniform size distribution. Functionalization with R8M at 58 \u00b5g\/mL preserved these characteristics when complexed with all mcDNA vectors. The formulations were biocompatible and effectively transfected DCs. Mannosylated formulations enhanced antigenic expression compared to non-mannosylated counterparts, evidencing a mannose-receptor-mediated uptake, while increasing the production of pro-inflammatory cytokines. Conclusions: Nanoparticles based on the RALA peptide and functionalized with R8M significantly improved mcDNA transfection and gene expression in APCs. These findings support further investigation of this system as a targeted DNA vector delivery platform against HPV-16.<\/jats:p>","DOI":"10.3390\/vaccines14010018","type":"journal-article","created":{"date-parts":[[2025,12,23]],"date-time":"2025-12-23T14:05:22Z","timestamp":1766498722000},"page":"18","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Development of RALA-Based Mannosylated Nanocarriers for Targeted Delivery of Minicircle DNA Vaccines Encoding HPV-16 Oncogenes"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0009-0004-3565-3340","authenticated-orcid":false,"given":"Andressa","family":"Giusti","sequence":"first","affiliation":[{"name":"RISE-Health, Department of Medical Sciences, Faculty of Health Sciences, University of Beira Interior, Av. Infante D. Henrique, 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":"RISE-Health, Department of Medical Sciences, Faculty of Health Sciences, University of Beira Interior, Av. Infante D. Henrique, 6200-506 Covilh\u00e3, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3428-9995","authenticated-orcid":false,"given":"Matilde","family":"Costa","sequence":"additional","affiliation":[{"name":"RISE-Health, Department of Medical Sciences, Faculty of Health Sciences, University of Beira Interior, Av. Infante D. Henrique, 6200-506 Covilh\u00e3, Portugal"}]},{"given":"In\u00eas","family":"Silveira","sequence":"additional","affiliation":[{"name":"RISE-Health, Department of Medical Sciences, Faculty of Health Sciences, University of Beira Interior, Av. Infante D. Henrique, 6200-506 Covilh\u00e3, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1575-4206","authenticated-orcid":false,"given":"Swati","family":"Biswas","sequence":"additional","affiliation":[{"name":"Nanomedicine Research Laboratory, Department of Pharmacy, Birla Institute of Technology and Science-Pilani, Hyderabad Campus, Jawahar Nagar, Medchal, Hyderabad 500078, India"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5049-4518","authenticated-orcid":false,"given":"Diana","family":"Costa","sequence":"additional","affiliation":[{"name":"RISE-Health, Department of Medical Sciences, Faculty of Health Sciences, University of Beira Interior, Av. Infante D. Henrique, 6200-506 Covilh\u00e3, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9155-7581","authenticated-orcid":false,"given":"\u00c2ngela","family":"Sousa","sequence":"additional","affiliation":[{"name":"RISE-Health, Department of Medical Sciences, Faculty of Health Sciences, University of Beira Interior, Av. Infante D. Henrique, 6200-506 Covilh\u00e3, Portugal"}]}],"member":"1968","published-online":{"date-parts":[[2025,12,23]]},"reference":[{"key":"ref_1","first-page":"378","article-title":"Cervical Cancer: A Health Limiting Condition","volume":"6","author":"Ci","year":"2016","journal-title":"Gynecol. Obs."},{"key":"ref_2","first-page":"229","article-title":"Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries","volume":"74","author":"Bray","year":"2024","journal-title":"CA Cancer J. Clin."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1016\/j.mrrev.2016.07.002","article-title":"Human papillomavirus molecular biology","volume":"772","author":"Harden","year":"2017","journal-title":"Mut. Res. Rev. Mutat. 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