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The development of effective therapies for brain disorders is highly correlated with the ability of drugs or nanosystems to cross the blood\u2013brain barrier (BBB), which has been limited. Recently, carbon dots (CDs) have been receiving attention to be used as BBB-crossing theranostic agents due to their inherent advantages, such as low size, excellent biocompatibility, high quantum yield (QY), tunable fluorescence, high drug loading, and relatively easy synthesis at low cost. The aim of this study was to design CDs with precisely controlled fluorescence properties for advanced bioimaging and an in-depth assessment of BBB permeability. Methods: CDs were synthesized using a microwave-assisted approach, optimized through microwaves\u2019 irradiation time, and employing citric acid, urea, and sodium fluoride as precursors. The optimized sample was labeled as NF-CD. Results: A comprehensive physicochemical, photoluminescence, and biological characterization revealed the ability of NF-CD to diffuse across a neuromimetic-BBB model, mainly due to their small size (average diameter of 4.0 \u00b1 1.1 nm), exhibiting excitation-dependent fluorescence in the blue and green wavelengths, high biocompatibility and QY, and exceptional photostability. Conclusions: Owing to the exceptional fluorescence characteristics and biological compatibility, NF-CD presents promising opportunities in theranostic applications, particularly in brain-targeted bioimaging, nanocarrier-based drug and immunotherapy delivery, early-stage diagnostics, and personalized medicine. NF-CD\u2019s ability to cross the BBB further underscores the relevance of pioneering nanomaterial-based strategies for neurological disorder diagnostics and precision-targeted therapeutic interventions. Overall, this research contributes to the broader field of nanotechnology-driven biomedical advancements, fostering innovations in neurological diagnostics and therapeutic delivery systems.<\/jats:p>","DOI":"10.3390\/pharmaceutics17040477","type":"journal-article","created":{"date-parts":[[2025,4,8]],"date-time":"2025-04-08T05:59:00Z","timestamp":1744091940000},"page":"477","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Carbon Dots as a Fluorescent Nanosystem for Crossing the Blood\u2013Brain Barrier with Plausible Application in Neurological Diseases"],"prefix":"10.3390","volume":"17","author":[{"given":"Catarina","family":"Ara\u00fajo","sequence":"first","affiliation":[{"name":"LSRE-LCM \u2014 Laboratory of Separation and Reaction Engineering - Laboratory of Catalysis and Materials, Faculty of Engineering, University of Porto, Rua Dr. Roberto Frias, 4200-465 Porto, Portugal"},{"name":"ALiCE \u2014 Associate Laboratory in Chemical Engineering, Faculty of Engineering, University of Porto, Rua Dr. Roberto Frias, 4200-465 Porto, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4493-2654","authenticated-orcid":false,"given":"Raquel O.","family":"Rodrigues","sequence":"additional","affiliation":[{"name":"Center for MicroElectromechanical Systems (CMEMS-UMinho), University of Minho, Campus de Azur\u00e9m, 4800-058 Guimar\u00e3es, Portugal"},{"name":"LABBELS\u2014Associate Laboratory, Braga\/Guimar\u00e3es, Portugal"},{"name":"International Iberian Nanotechnology Laboratory (INL), Av. Mestre Jos\u00e9 Veiga s\/n, 4715-330 Braga, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4319-2631","authenticated-orcid":false,"given":"Manuel","family":"Ba\u00f1obre-L\u00f3pez","sequence":"additional","affiliation":[{"name":"International Iberian Nanotechnology Laboratory (INL), Av. Mestre Jos\u00e9 Veiga s\/n, 4715-330 Braga, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8551-6353","authenticated-orcid":false,"given":"Adri\u00e1n M. T.","family":"Silva","sequence":"additional","affiliation":[{"name":"LSRE-LCM \u2014 Laboratory of Separation and Reaction Engineering - Laboratory of Catalysis and Materials, Faculty of Engineering, University of Porto, Rua Dr. Roberto Frias, 4200-465 Porto, Portugal"},{"name":"ALiCE \u2014 Associate Laboratory in Chemical Engineering, Faculty of Engineering, University of Porto, Rua Dr. Roberto Frias, 4200-465 Porto, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2314-0447","authenticated-orcid":false,"given":"Rui S.","family":"Ribeiro","sequence":"additional","affiliation":[{"name":"LSRE-LCM \u2014 Laboratory of Separation and Reaction Engineering - Laboratory of Catalysis and Materials, Faculty of Engineering, University of Porto, Rua Dr. Roberto Frias, 4200-465 Porto, Portugal"},{"name":"ALiCE \u2014 Associate Laboratory in Chemical Engineering, Faculty of Engineering, University of Porto, Rua Dr. Roberto Frias, 4200-465 Porto, Portugal"}]}],"member":"1968","published-online":{"date-parts":[[2025,4,6]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1577","DOI":"10.1016\/S0140-6736(20)32205-4","article-title":"Alzheimer\u2019s disease","volume":"397","author":"Scheltens","year":"2021","journal-title":"Lancet"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.canlet.2020.02.002","article-title":"Immunotherapy for glioma: Current management and future application","volume":"476","author":"Xu","year":"2020","journal-title":"Cancer Lett."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1406","DOI":"10.1039\/C7LC00103G","article-title":"Microfluidic neural probes: In vivo tools for advancing neuroscience","volume":"17","author":"Sim","year":"2017","journal-title":"Lab Chip"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1093","DOI":"10.1039\/c2lc41208j","article-title":"SyM-BBB: A microfluidic blood brain barrier model","volume":"13","author":"Prabhakarpandian","year":"2013","journal-title":"Lab Chip"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1007\/s10544-012-9699-7","article-title":"BBB ON CHIP: Microfluidic platform to mechanically and biochemically modulate blood-brain barrier function","volume":"15","author":"Griep","year":"2013","journal-title":"Biomed. 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