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Despite their widespread application, a comprehensive understanding of their intracellular trafficking remains elusive. In the present study, we focused on exploring the impact of a 20 nm difference in size on NP performance, including drug delivery capabilities and intracellular trafficking. For that, poly(ethylene glycol) methyl ether-block-poly(lactide-co-glycolide) (PLGA-PEG) NPs with sizes of 50 and 70 nm were precisely tailored. To assess their prowess in encapsulating and releasing therapeutic agents, we have employed doxorubicin (Dox), a well-established anticancer drug widely utilized in clinical settings, as a model drug. Then, the beneficial effect of the developed nanoformulations was evaluated in breast cancer cells. Finally, we performed a semiquantitative analysis of both NPs\u2019 uptake and intracellular localization by immunostaining lysosomes, early endosomes, and recycling endosomes. The results show that the smaller NPs (50 nm) were able to reduce the metabolic activity of cancer cells more efficiently than NPs of 70 nm, in a time and concentration-dependent manner. These findings are corroborated by intracellular trafficking studies that reveal an earlier and higher uptake of NPs, with 50 nm compared to the 70 nm ones, by the breast cancer cells. Consequently, this study demonstrates that NP size, even in small increments, has an important impact on their therapeutic effect.<\/jats:p>","DOI":"10.3390\/ijms25010312","type":"journal-article","created":{"date-parts":[[2023,12,25]],"date-time":"2023-12-25T23:00:12Z","timestamp":1703545212000},"page":"312","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Intracellular Trafficking of Size-Tuned Nanoparticles for Drug Delivery"],"prefix":"10.3390","volume":"25","author":[{"given":"Sara","family":"Gimondi","sequence":"first","affiliation":[{"name":"3B\u2019s Research Group, I3Bs\u2014Research Institute on Biomaterials, Biodegradables and Biomimetics, University of Minho, Headquarters of the European Institute of Excellence on Tissue Engineering and Regenerative Medicine, AvePark, Parque de Ci\u00eancia e Tecnologia, Zona Industrial da Gandra, 4805-017 Guimar\u00e3es, Portugal"},{"name":"ICVS\/3B\u2019s\u2013PT Government Associate Laboratory, 4710-057 Guimar\u00e3es, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3770-9393","authenticated-orcid":false,"given":"Helena","family":"Ferreira","sequence":"additional","affiliation":[{"name":"3B\u2019s Research Group, I3Bs\u2014Research Institute on Biomaterials, Biodegradables and Biomimetics, University of Minho, Headquarters of the European Institute of Excellence on Tissue Engineering and Regenerative Medicine, AvePark, Parque de Ci\u00eancia e Tecnologia, Zona Industrial da Gandra, 4805-017 Guimar\u00e3es, Portugal"},{"name":"ICVS\/3B\u2019s\u2013PT Government Associate Laboratory, 4710-057 Guimar\u00e3es, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4295-6129","authenticated-orcid":false,"given":"Rui L.","family":"Reis","sequence":"additional","affiliation":[{"name":"3B\u2019s Research Group, I3Bs\u2014Research Institute on Biomaterials, Biodegradables and Biomimetics, University of Minho, Headquarters of the European Institute of Excellence on Tissue Engineering and Regenerative Medicine, AvePark, Parque de Ci\u00eancia e Tecnologia, Zona Industrial da Gandra, 4805-017 Guimar\u00e3es, Portugal"},{"name":"ICVS\/3B\u2019s\u2013PT Government Associate Laboratory, 4710-057 Guimar\u00e3es, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3041-0687","authenticated-orcid":false,"given":"Nuno M.","family":"Neves","sequence":"additional","affiliation":[{"name":"3B\u2019s Research Group, I3Bs\u2014Research Institute on Biomaterials, Biodegradables and Biomimetics, University of Minho, Headquarters of the European Institute of Excellence on Tissue Engineering and Regenerative Medicine, AvePark, Parque de Ci\u00eancia e Tecnologia, Zona Industrial da Gandra, 4805-017 Guimar\u00e3es, Portugal"},{"name":"ICVS\/3B\u2019s\u2013PT Government Associate Laboratory, 4710-057 Guimar\u00e3es, Portugal"}]}],"member":"1968","published-online":{"date-parts":[[2023,12,25]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"160","DOI":"10.1186\/s12943-023-01849-0","article-title":"Lipid Polymer Hybrid Nanoparticles: A Custom-Tailored next-Generation Approach for Cancer Therapeutics","volume":"22","author":"Gajbhiye","year":"2023","journal-title":"Mol. 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