{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,3]],"date-time":"2026-07-03T19:51:21Z","timestamp":1783108281902,"version":"3.54.6"},"reference-count":30,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2021,3,18]],"date-time":"2021-03-18T00:00:00Z","timestamp":1616025600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2021,3,18]],"date-time":"2021-03-18T00:00:00Z","timestamp":1616025600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100008385","name":"Fondazione per la Ricerca sulla Fibrosi Cistica","doi-asserted-by":"publisher","award":["FFC#1\/2020"],"award-info":[{"award-number":["FFC#1\/2020"]}],"id":[{"id":"10.13039\/501100008385","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Cystic fibrosis (CF) is characterized by an airway obstruction caused by a thick mucus due to a malfunctioning Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) protein. The sticky mucus restricts drugs in reaching target cells limiting the efficiency of treatments. The development of new approaches to enhance drug delivery to the lungs represents CF treatment's main challenge. In this work, we report the production and characterization of hybrid core\u2013shell nanoparticles (hNPs) comprising a PLGA core and a dipalmitoylphosphatidylcholine (DPPC) shell engineered for inhalation. We loaded hNPs with a 7-mer peptide nucleic acid (PNA) previously considered for its ability to modulate the post-transcriptional regulation of the CFTR gene. We also investigated the in vitro release kinetics of hNPs and their efficacy in PNA delivery across the human epithelial airway barrier using an ex vivo model based on human primary nasal epithelial cells (HNEC) from CF patients. Confocal analyses and hNPs transport assay demonstrated the ability of hNPs to overcome the mucus barrier and release their PNA cargo within the cytoplasm, where it can exert\u00a0its biological function.<\/jats:p>","DOI":"10.1038\/s41598-021-85549-z","type":"journal-article","created":{"date-parts":[[2021,3,18]],"date-time":"2021-03-18T12:47:41Z","timestamp":1616071661000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":22,"title":["Assisting PNA transport through cystic fibrosis human airway epithelia with biodegradable hybrid lipid-polymer nanoparticles"],"prefix":"10.1038","volume":"11","author":[{"given":"Marika","family":"Comegna","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gemma","family":"Conte","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea Patrizia","family":"Falanga","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria","family":"Marzano","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gustavo","family":"Cernera","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antonella Miriam","family":"Di Lullo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Felice","family":"Amato","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicola","family":"Borbone","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefano","family":"D\u2019Errico","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesca","family":"Ungaro","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ivana","family":"d\u2019Angelo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giorgia","family":"Oliviero","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giuseppe","family":"Castaldo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,3,18]]},"reference":[{"key":"85549_CR1","doi-asserted-by":"publisher","first-page":"82","DOI":"10.1016\/j.addr.2017.10.009","volume":"124","author":"X Murgia","year":"2018","unstructured":"Murgia, X., Loretz, B., Hartwig, O., Hittinger, M. & Lehr, C. M. The role of mucus on drug transport and its potential to affect therapeutic outcomes. Adv. Drug Deliv. Rev. 124, 82\u201397 (2018).","journal-title":"Adv. Drug Deliv. Rev."},{"key":"85549_CR2","doi-asserted-by":"publisher","first-page":"1891","DOI":"10.1016\/S0140-6736(09)60327-5","volume":"373","author":"BP O\u2019Sullivan","year":"2009","unstructured":"O\u2019Sullivan, B. P. & Freedman, S. D. Cystic fibrosis. Lancet 373, 1891\u20131904 (2009).","journal-title":"Lancet"},{"key":"85549_CR3","doi-asserted-by":"publisher","first-page":"453","DOI":"10.1038\/s41598-019-57289-8","volume":"10","author":"CMA Gangemi","year":"2020","unstructured":"Gangemi, C. M. A. et al. Endogenous and artificial miRNAs explore a rich variety of conformations: a potential relationship between secondary structure and biological functionality. Sci. Rep. 10, 453 (2020).","journal-title":"Sci. Rep."},{"key":"85549_CR4","doi-asserted-by":"publisher","first-page":"1416","DOI":"10.1016\/j.bcp.2011.08.007","volume":"82","author":"R Gambari","year":"2011","unstructured":"Gambari, R. et al. Targeting microRNAs involved in human diseases\u202f: A novel approach for modification of gene expression and drug development. Biochem. Pharmacol. 82, 1416\u20131429 (2011).","journal-title":"Biochem. Pharmacol."},{"key":"85549_CR5","doi-asserted-by":"publisher","first-page":"1144","DOI":"10.3390\/molecules22071144","volume":"22","author":"F Zarrilli","year":"2017","unstructured":"Zarrilli, F. et al. Peptide nucleic acids as miRNA target protectors for the treatment of cystic fibrosis. Molecules 22, 1144 (2017).","journal-title":"Molecules"},{"key":"85549_CR6","doi-asserted-by":"publisher","first-page":"68","DOI":"10.1039\/C3MD00257H","volume":"5","author":"F Amato","year":"2014","unstructured":"Amato, F. et al. Design, synthesis and biochemical investigation, by in vitro luciferase reporter system, of peptide nucleic acids as new inhibitors of miR-509-3p involved in the regulation of cystic fibrosis disease-gene expression. Med. Chem. Commun. 5, 68\u201371 (2014).","journal-title":"Med. Chem. Commun."},{"key":"85549_CR7","doi-asserted-by":"publisher","first-page":"e60448","DOI":"10.1371\/journal.pone.0060448","volume":"8","author":"F Amato","year":"2013","unstructured":"Amato, F. et al. Gene mutation in MicroRNA target sites of CFTR gene: A novel pathogenetic mechanism in cystic fibrosis?. PLoS ONE 8, e60448 (2013).","journal-title":"PLoS ONE"},{"key":"85549_CR8","doi-asserted-by":"publisher","first-page":"610718","DOI":"10.1155\/2014\/610718","volume":"2014","author":"F Amato","year":"2014","unstructured":"Amato, F. et al. Exploitation of a very small peptide nucleic acid as a new inhibitor of miR-509-3p involved in the regulation of cystic fibrosis disease-gene expression. Biomed Res. Int. 2014, 610718 (2014).","journal-title":"Biomed Res. Int."},{"key":"85549_CR9","doi-asserted-by":"publisher","first-page":"16","DOI":"10.1111\/cbdd.12833","volume":"89","author":"C Sharma","year":"2017","unstructured":"Sharma, C. & Awasthi, S. K. Versatility of peptide nucleic acids (PNAs): Role in chemical biology, drug discovery, and origins of life. Chem. Biol. Drug Des. 89, 16\u201337 (2017).","journal-title":"Chem. Biol. Drug Des."},{"key":"85549_CR10","doi-asserted-by":"publisher","first-page":"1299","DOI":"10.1021\/bc0501606","volume":"16","author":"J D\u2019Onofrio","year":"2005","unstructured":"D\u2019Onofrio, J., de Champdor\u00e9, M., De Napoli, L., Montesarchio, D. & Di Fabio, G. Glycomimetics as decorating motifs for oligonucleotides: Solid-phase synthesis, stability, and hybridization properties of carbopeptoid\u2212oligonucleotide conjugates. Bioconjug. Chem. 16, 1299\u20131309 (2005).","journal-title":"Bioconjug. Chem."},{"key":"85549_CR11","doi-asserted-by":"crossref","unstructured":"de Koning, M. C., vad der Marel, G. A. & Overhand, M. Synthetic developments towards PNA peptide conjugates. Curr. Opin. Chem. Biol. 7, 734\u2013740 (2003).","DOI":"10.1016\/j.cbpa.2003.10.006"},{"key":"85549_CR12","doi-asserted-by":"publisher","first-page":"654","DOI":"10.1021\/bc100444v","volume":"22","author":"J Amato","year":"2011","unstructured":"Amato, J., Pagano, B., Borbone, N., Oliviero, G. & Gabelica, V. Targeting G-quadruplex structure in the human c-kit promoter with short PNA sequences. Bioconjug. Chem. 22, 654\u2013663 (2011).","journal-title":"Bioconjug. Chem."},{"key":"85549_CR13","doi-asserted-by":"publisher","first-page":"572","DOI":"10.1021\/acs.bioconjchem.8b00674","volume":"30","author":"AP Falanga","year":"2019","unstructured":"Falanga, A. P. et al. Peptide nucleic acid-functionalized adenoviral vectors targeting G-quadruplexes in the P1 promoter of Bcl-2 proto-oncogene: A new tool for gene modulation in anticancer therapy. Bioconjug. Chem. 30, 572\u2013582 (2019).","journal-title":"Bioconjug. Chem."},{"key":"85549_CR14","first-page":"1","volume":"1","author":"CG Janson","year":"2006","unstructured":"Janson, C. G. & During, M. J. Peptide nucleic acids, morpholinos and related antisense biomolecules. Med. Intell. unit 1, 1\u2013274 (2006).","journal-title":"Med. Intell. unit"},{"key":"85549_CR15","doi-asserted-by":"publisher","first-page":"267","DOI":"10.1016\/S0169-409X(02)00182-5","volume":"55","author":"U Koppelhus","year":"2003","unstructured":"Koppelhus, U. & Nielsen, P. E. Cellular delivery of peptide nucleic acid (PNA). Adv. Drug Deliv. Rev. 55, 267\u2013280 (2003).","journal-title":"Adv. Drug Deliv. Rev."},{"key":"85549_CR16","doi-asserted-by":"publisher","first-page":"386","DOI":"10.2174\/1568026615666150108123256","volume":"15","author":"I d\u2019Angelo","year":"2015","unstructured":"d\u2019Angelo, I., Conte, C., Miro, A., Quaglia, F. & Ungaro, F. Pulmonary drug delivery: A role for polymeric nanoparticles?. Curr. Top. Med. Chem. 15, 386\u2013400 (2015).","journal-title":"Curr. Top. Med. Chem."},{"key":"85549_CR17","doi-asserted-by":"publisher","first-page":"119671","DOI":"10.1016\/j.ijpharm.2020.119671","volume":"587","author":"T Praphawatvet","year":"2020","unstructured":"Praphawatvet, T., Peters, J. I. & Williams, R. O. Inhaled nanoparticles\u2013An updated review. Int. J. Pharm. 587, 119671 (2020).","journal-title":"Int. J. Pharm."},{"key":"85549_CR18","doi-asserted-by":"publisher","first-page":"150","DOI":"10.1016\/j.drudis.2019.09.023","volume":"25","author":"Q Liu","year":"2020","unstructured":"Liu, Q., Guan, J., Qin, L., Zhang, X. & Mao, S. Physicochemical properties affecting the fate of nanoparticles in pulmonary drug delivery. Drug Discov. Today 25, 150\u2013159 (2020).","journal-title":"Drug Discov. Today"},{"key":"85549_CR19","doi-asserted-by":"publisher","first-page":"48","DOI":"10.1016\/j.jconrel.2019.10.035","volume":"314","author":"Y He","year":"2019","unstructured":"He, Y. et al. Rational particle design to overcome pulmonary barriers for obstructive lung diseases therapy. J. Control. Release 314, 48\u201361 (2019).","journal-title":"J. Control. Release"},{"key":"85549_CR20","doi-asserted-by":"crossref","unstructured":"Velino, C. et al. Nanomedicine approaches for the pulmonary treatment of cystic fibrosis. Front. Bioeng. Biotechnol. 7 (2019).","DOI":"10.3389\/fbioe.2019.00406"},{"key":"85549_CR21","doi-asserted-by":"publisher","first-page":"170","DOI":"10.1089\/jamp.2017.1364","volume":"31","author":"I d\u2019Angelo","year":"2018","unstructured":"d\u2019Angelo, I. et al. Hybrid lipid\/polymer nanoparticles for pulmonary delivery of siRNA: Development and fate upon in vitro deposition on the human epithelial airway barrier. J. Aerosol Med. Pulm. Drug Deliv. 31, 170\u2013181 (2018).","journal-title":"J. Aerosol Med. Pulm. Drug Deliv."},{"key":"85549_CR22","doi-asserted-by":"crossref","first-page":"207","DOI":"10.14639\/0392-100X-1328","volume":"37","author":"AM Di Lullo","year":"2017","unstructured":"Di Lullo, A. M. et al. An \u2018ex vivo model\u2019 contributing to the diagnosis and evaluation of new drugs in cystic fibrosis. Acta Otorhinolaryngol. Ital. 37, 207\u2013213 (2017).","journal-title":"Acta Otorhinolaryngol. Ital."},{"key":"85549_CR23","doi-asserted-by":"publisher","first-page":"742","DOI":"10.1002\/humu.23741","volume":"40","author":"F Amato","year":"2019","unstructured":"Amato, F. et al. Two CFTR mutations within codon 970 differently impact on the chloride channel functionality. Hum. Mutat. 40, 742\u2013748 (2019).","journal-title":"Hum. Mutat."},{"key":"85549_CR24","doi-asserted-by":"crossref","unstructured":"Brewington, J. J. et al. Brushed nasal epithelial cells are a surrogate for bronchial epithelial CFTR studies. JCI Insight 3 (2018).","DOI":"10.1172\/jci.insight.99385"},{"key":"85549_CR25","doi-asserted-by":"publisher","first-page":"172","DOI":"10.1038\/mt.2010.200","volume":"19","author":"NA McNeer","year":"2011","unstructured":"McNeer, N. A. et al. Nanoparticles deliver triplex-forming PNAs for site-specific genomic recombination in CD34+ human hematopoietic progenitors. Mol. Ther. 19, 172\u2013180 (2011).","journal-title":"Mol. Ther."},{"key":"85549_CR26","doi-asserted-by":"publisher","first-page":"658","DOI":"10.1038\/gt.2012.82","volume":"20","author":"NA McNeer","year":"2013","unstructured":"McNeer, N. A. et al. Systemic delivery of triplex-forming PNA and donor DNA by nanoparticles mediates site-specific genome editing of human hematopoietic cells in vivo. Gene Ther. 20, 658\u2013669 (2013).","journal-title":"Gene Ther."},{"key":"85549_CR27","doi-asserted-by":"publisher","first-page":"6952","DOI":"10.1038\/ncomms7952","volume":"6","author":"NA McNeer","year":"2015","unstructured":"McNeer, N. A. et al. Nanoparticles that deliver triplex-forming peptide nucleic acid molecules correct F508del CFTR in airway epithelium. Nat. Commun. 6, 6952 (2015).","journal-title":"Nat. Commun."},{"key":"85549_CR28","doi-asserted-by":"publisher","first-page":"92","DOI":"10.1016\/j.addr.2014.05.008","volume":"75","author":"I d\u2019Angelo","year":"2014","unstructured":"d\u2019Angelo, I. et al. Improving the efficacy of inhaled drugs in cystic fibrosis: Challenges and emerging drug delivery strategies. Adv. Drug Deliv. Rev. 75, 92\u2013111 (2014).","journal-title":"Adv. Drug Deliv. Rev."},{"key":"85549_CR29","doi-asserted-by":"publisher","first-page":"288","DOI":"10.1165\/rcmb.2012-0473OC","volume":"49","author":"D De Stefano","year":"2013","unstructured":"De Stefano, D.  et al. A decoy oligonucleotide to NF-\u03baB delivered through inhalable particles prevents LPS-induced rat airway inflammation. Am. J. Respir. Cell Mol. Biol. 49, 288\u2013295 (2013).","journal-title":"Am. J. Respir. Cell Mol. Bio"},{"key":"85549_CR30","doi-asserted-by":"publisher","first-page":"671","DOI":"10.1038\/nmeth.2089","volume":"9","author":"CA Schneider","year":"2012","unstructured":"Schneider, C. A., Rasband, W. S. & Eliceiri, K. W. NIH Image to ImageJ: 25 years of image analysis. Nat. Methods 9, 671\u2013675 (2012).","journal-title":"Nat. Methods"}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-021-85549-z.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-021-85549-z","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-021-85549-z.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,3]],"date-time":"2022-12-03T00:43:07Z","timestamp":1670028187000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-021-85549-z"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,3,18]]},"references-count":30,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2021,12]]}},"alternative-id":["85549"],"URL":"https:\/\/doi.org\/10.1038\/s41598-021-85549-z","relation":{"has-preprint":[{"id-type":"doi","id":"10.21203\/rs.3.rs-111943\/v1","asserted-by":"object"}]},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,3,18]]},"assertion":[{"value":"19 November 2020","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"1 March 2021","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"18 March 2021","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"6393"}}