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disorders. However, their therapeutic application is limited by poor stability and bioavailability. This study aimed to develop and characterize nanomicelles encapsulating LXA4 (nano-lipoxin A4) to improve its pharmacological efficacy against Alzheimer\u2019s disease (AD), a neurodegenerative condition marked by chronic inflammation and beta-amyloid (A\u03b2) accumulation. Methods: Nano-lipoxin A4 was synthesized using Pluronic F-127 as a carrier and characterized in terms of morphology, physicochemical stability, and in vitro activity against A\u03b2 fibrils. Dissociation of A\u03b2 fibrils was assessed via Thioflavin-T fluorescence assays and transmission electron microscopy. In vivo biodistribution and pharmacokinetic profiles were evaluated using technetium-99m-labeled nano-lipoxin A4 in rodent models. Hepatic biochemical parameters were also measured to assess potential systemic effects. Results: In vitro studies demonstrated that nano-lipoxin A4 effectively dissociated A\u03b2 fibrils at concentrations of 50 nM and 112 nM. Electron microscopy confirmed the disruption of fibrillar structures. In vivo imaging revealed predominant accumulation in the liver and spleen, consistent with reticuloendothelial system uptake. Pharmacokinetic analysis showed a prolonged half-life (63.95 h) and low clearance rate (0.001509 L\/h), indicating sustained systemic presence. Biochemical assays revealed elevated liver enzyme levels, suggestive of increased hepatic metabolism or potential hepatotoxicity. Conclusions: Nano-lipoxin A4 exhibits significant therapeutic potential for Alzheimer\u2019s disease through effective modulation of A\u03b2 pathology and favorable pharmacokinetic characteristics. However, the elevation in liver enzymes necessitates further investigation into systemic safety to support clinical translation.<\/jats:p>","DOI":"10.3390\/pharmaceutics17050649","type":"journal-article","created":{"date-parts":[[2025,5,15]],"date-time":"2025-05-15T06:59:16Z","timestamp":1747292356000},"page":"649","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Nanostructured Lipoxin A4: Understanding Its Biological Behavior and Impact on Alzheimer\u2019s Disease (Proof of Concept)"],"prefix":"10.3390","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9088-6671","authenticated-orcid":false,"given":"Nat\u00e1lia Cristina","family":"Gomes-da-Silva","sequence":"first","affiliation":[{"name":"Laboratory of Nanoradiopharmacy and Synthesis of New Radiopharmaceuticals, Nuclear Engineering Institute, Brazilian Nuclear Energy Commission, Rio de Janeiro 21941906, RJ, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-6962-9173","authenticated-orcid":false,"given":"Isabelle","family":"Xavier-de-Britto","sequence":"additional","affiliation":[{"name":"Laboratory of Nanoradiopharmacy and Synthesis of New Radiopharmaceuticals, Nuclear Engineering Institute, Brazilian Nuclear Energy Commission, Rio de Janeiro 21941906, RJ, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2390-8428","authenticated-orcid":false,"given":"Marilia Am\u00e1vel Gomes","family":"Soares","sequence":"additional","affiliation":[{"name":"Laboratory of Nanoradiopharmacy and Synthesis of New Radiopharmaceuticals, Nuclear Engineering Institute, Brazilian Nuclear Energy Commission, Rio de Janeiro 21941906, RJ, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Natalia Mayumi Andrade","family":"Yoshihara","sequence":"additional","affiliation":[{"name":"Laboratory of Nanoradiopharmacy and Synthesis of New Radiopharmaceuticals, Nuclear Engineering Institute, Brazilian Nuclear Energy Commission, Rio de Janeiro 21941906, RJ, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Derya","family":"Ilem \u00d6zdemir","sequence":"additional","affiliation":[{"name":"Faculty of Pharmacy, Department of Radiopharmacy, Ege University, Bornova, Izmir 35040, Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2550-696X","authenticated-orcid":false,"given":"Eduardo","family":"Ricci-Junior","sequence":"additional","affiliation":[{"name":"School of Pharmacy, Federal University of Rio de Janeiro, Rio de Janeiro 21941900, RJ, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7822-2354","authenticated-orcid":false,"given":"Pierre Bas\u00edlio Almeida","family":"Fechine","sequence":"additional","affiliation":[{"name":"Group of Chemistry of Advanced Materials (GQMat), Department of Analytical Chemistry and Physical-Chemistry, Federal University of Cear\u00e1, Fortaleza 451970, CE, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8210-2016","authenticated-orcid":false,"given":"Luciana Magalh\u00e3es Rebelo","family":"Alencar","sequence":"additional","affiliation":[{"name":"Biophysics and Nanosystems Laboratory, Department of Physics, Federal University of Maranh\u00e3o, S\u00e3o Luis 65065690, MA, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3065-0541","authenticated-orcid":false,"given":"Maria das Gra\u00e7as Muller de Oliveira","family":"Henriques","sequence":"additional","affiliation":[{"name":"Laboratory of Cellular & Molecular Pharmacology, Department of Cell Biology, Instituto de Biologia Roberto Alcantara Gomes (IBRAG), Universidade do Estado do Rio de Janeiro, Rio de Janeiro 20551030, RJ, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1917-4401","authenticated-orcid":false,"given":"Thereza Christina","family":"Barja-Fidalgo","sequence":"additional","affiliation":[{"name":"Laboratory of Cellular & Molecular Pharmacology, Department of Cell Biology, Instituto de Biologia Roberto Alcantara Gomes (IBRAG), Universidade do Estado do Rio de Janeiro, Rio de Janeiro 20551030, RJ, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6178-0432","authenticated-orcid":false,"given":"Cristian","family":"Follmer","sequence":"additional","affiliation":[{"name":"Laboratory of Biological Chemistry of Neurodegenerative Disorders, Department of Physical Chemistry, Institute of Chemistry, Federal University of Rio de Janeiro, Rio de Janeiro 21941909, RJ, 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