{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,24]],"date-time":"2026-10-24T00:52:34Z","timestamp":1792803154432,"version":"4.5.0"},"reference-count":41,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,6,17]],"date-time":"2026-06-17T00:00:00Z","timestamp":1781654400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100018553","name":"Science and Technology Plan Project of Wenzhou Municipality","doi-asserted-by":"publisher","award":["Y2023188"],"award-info":[{"award-number":["Y2023188"]}],"id":[{"id":"10.13039\/501100018553","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100017594","name":"Medical Science and Technology Project of Zhejiang Province","doi-asserted-by":"publisher","award":["2025KY1513"],"award-info":[{"award-number":["2025KY1513"]}],"id":[{"id":"10.13039\/501100017594","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Chem."],"abstract":"\n Nicotinamide mononucleotide (NMN) has anti-inflammatory, antioxidant, and mitochondrial function-enhancing properties, which demonstrate its significant neuroprotective potential. However, its high water solubility presents challenges with regard to blood-brain barrier (BBB) permeability, prompting extensive research interest. This study used a composite emulsification method combined with response surface methodology to optimize the formulation and preparation process, resulting in the design of lactoferrin (Lf)-modified lipid nanoparticles (LNPs)\u2014NMN-LNPs-Lf. LNPs prepared under optimal conditions exhibited spherical morphology with an average particle size of approximately 147\u00a0nm, achieving a drug loading capacity of 5.02%, and a Lf modification rate of 41.8%. Using the mouse brain endothelial cell line 3 (bEnd.3) experimental results demonstrated that NMN-LNPs-Lf significantly enhanced NMN\u2019s BBB permeability without inducing notable cytotoxicity, achieving a BBB permeability rate of 62%. This permeability was markedly higher than that of conventional unmodified NMN-LNPs and NMN active pharmaceutical ingredients (\n P<\/jats:italic>\n &lt; 0.01). NMN-LNPs-Lf significantly altered the pharmacokinetic and tissue distribution in rats. Under identical dosing regimens, the\n \n \n \n \n AUC<\/mml:mtext>\n \n \n \n \n 0<\/mml:mn>\n \u2212<\/mml:mo>\n <\/mml:mrow>\n \u221e<\/mml:mi>\n <\/mml:mrow>\n <\/mml:mfenced>\n <\/mml:mrow>\n <\/mml:msub>\n <\/mml:mrow>\n <\/mml:math>\n <\/jats:inline-formula>\n , Vz\/F, CLz\/F, C\n max<\/jats:sub>\n , and\n \n \n \n \n MRT<\/mml:mtext>\n \n \n \n \n 0<\/mml:mn>\n \u2212<\/mml:mo>\n <\/mml:mrow>\n \u221e<\/mml:mi>\n <\/mml:mrow>\n <\/mml:mfenced>\n <\/mml:mrow>\n <\/mml:msub>\n <\/mml:mrow>\n <\/mml:math>\n <\/jats:inline-formula>\n were significantly higher than API (\n P<\/jats:italic>\n &lt; 0.01), accompanied by selective NMN enrichment in brain tissue. Overall, NMN-LNPs-Lf demonstrated an enhanced capacity for brain-targeting delivery in both\n in vitro<\/jats:italic>\n cell models and normal rats, suggesting its potential as a therapeutic strategy for neurodegenerative diseases. Future research should incorporate pathological models to conduct in-depth functional and mechanistic evaluations.\n <\/jats:p>","DOI":"10.3389\/fchem.2026.1759167","type":"journal-article","created":{"date-parts":[[2026,6,17]],"date-time":"2026-06-17T04:50:14Z","timestamp":1781671814000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Brain-targeting lipid nanoparticles of nicotinamide mononucleotide: preparation, optimization, and characterization"],"prefix":"10.3389","volume":"14","author":[{"given":"Yuxian","family":"Lin","sequence":"first","affiliation":[{"name":"School of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), Ministry of Education, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Yantai University","place":["Yantai, Shandong, China"]},{"name":"The Third Clinical Institute Affiliated to Wenzhou Medical University, Wenzhou People\u2019s Hospital","place":["Wenzhou, Zhejiang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fengdong","family":"Zhao","sequence":"additional","affiliation":[{"name":"School of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), Ministry of Education, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Yantai University","place":["Yantai, Shandong, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinhui","family":"Wang","sequence":"additional","affiliation":[{"name":"The Third Clinical Institute Affiliated to Wenzhou Medical University, Wenzhou People\u2019s Hospital","place":["Wenzhou, Zhejiang, China"]},{"name":"Department of Hepatobiliary Surgery, The First Affiliated Hospital of Wenzhou Medical University","place":["Wenzhou, Zhejiang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Songyuge","family":"Ping","sequence":"additional","affiliation":[{"name":"School of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), Ministry of Education, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Yantai University","place":["Yantai, Shandong, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kaihan","family":"Wu","sequence":"additional","affiliation":[{"name":"School of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), Ministry of Education, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Yantai University","place":["Yantai, Shandong, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yangfang","family":"Chen","sequence":"additional","affiliation":[{"name":"The Third Clinical Institute Affiliated to Wenzhou Medical University, Wenzhou People\u2019s Hospital","place":["Wenzhou, Zhejiang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiang","family":"Zheng","sequence":"additional","affiliation":[{"name":"The Third Clinical Institute Affiliated to Wenzhou Medical University, Wenzhou People\u2019s Hospital","place":["Wenzhou, Zhejiang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hui","family":"Xu","sequence":"additional","affiliation":[{"name":"School of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), Ministry of Education, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Yantai University","place":["Yantai, Shandong, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,6,17]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"508","DOI":"10.3390\/polym14030508","article-title":"Experimental design and optimization of nano-transfersomal gel to enhance the hypoglycemic activity of silymarin","volume":"14","author":"Abdallah","year":"2022","journal-title":"Polym. (Basel)"},{"key":"B2","doi-asserted-by":"publisher","first-page":"19335","DOI":"10.1039\/d4nr02934h","article-title":"A biocompatible polydopamine platform for targeted delivery of nicotinamide mononucleotide and boosting NAD+ levels in the brain","volume":"16","author":"Cai","year":"2024","journal-title":"Nanoscale"},{"key":"B3","doi-asserted-by":"publisher","first-page":"125054","DOI":"10.1016\/j.ijpharm.2024.125054","article-title":"Bromocriptine mesylate-loaded nanoparticles co-modified with low molecular weight protamine and lactoferrin for enhanced nose-to-brain delivery in parkinson's disease treatment","volume":"669","author":"Cong","year":"2025","journal-title":"Int. J. Pharm."},{"key":"B4","doi-asserted-by":"publisher","first-page":"32","DOI":"10.2174\/0115733998291968240429111357","article-title":"Unraveling the ties: type 2 diabetes and Parkinson'S disease - a nano-based targeted drug delivery approach","volume":"21","author":"De","year":"2025","journal-title":"Curr. Diabetes Rev."},{"key":"B5","doi-asserted-by":"publisher","first-page":"7565","DOI":"10.1007\/s00289-025-05881-6","article-title":"Navigating into the paradigm of lactoferrin surface modified nanocarriers in the management of central nervous system disorders","volume":"82","author":"Desai","year":"2025","journal-title":"Polym. Bull."},{"key":"B6","doi-asserted-by":"publisher","first-page":"1204149","DOI":"10.3389\/fnagi.2023.1204149","article-title":"Lactoferrin: neuroprotection against parkinson\u2019s disease and secondary molecule for potential treatment","volume":"15","author":"Eker","year":"2023","journal-title":"Front. Aging Neurosci."},{"key":"B7","doi-asserted-by":"publisher","first-page":"661","DOI":"10.3390\/pharmaceutics17050661","article-title":"Advancing brain targeting: cost-effective surface-modified nanoparticles for faster market entry","volume":"17","author":"Gomes","year":"2025","journal-title":"Pharmaceutics"},{"key":"B8","doi-asserted-by":"publisher","first-page":"1364","DOI":"10.1021\/acs.langmuir.3c03019","article-title":"Nanoemulsions stable against ostwald ripening","volume":"40","author":"Guo","year":"2024","journal-title":"Langmuir"},{"key":"B9","doi-asserted-by":"publisher","first-page":"156547","DOI":"10.1016\/j.phymed.2025.156547","article-title":"Lactoferrin-modified organic-inorganic hybrid mesoporous silica for co-delivery of levodopa and curcumin in the synergistic treatment of parkinson's disease","volume":"140","author":"Guo","year":"2025","journal-title":"Phytomedicine"},{"key":"B10","doi-asserted-by":"publisher","first-page":"169","DOI":"10.1080\/21691401.2017.1304403","article-title":"A comprehensive mathematical model of drug release kinetics from nano-liposomes, derived from optimization studies of cationic PEGylated liposomal doxorubicin formulations for drug-gene delivery","volume":"46","author":"Haghiralsadat","year":"2018","journal-title":"Artif. Cells Nanomed. Biotechnol."},{"key":"B11","doi-asserted-by":"publisher","first-page":"113878","DOI":"10.1016\/j.fct.2023.113878","article-title":"Nicotinamide mononucleotide (NMN) ameliorated Nonylphenol-induced learning and memory impairment in rats via the central 5-HT system and the NAD+\/SIRT1\/MAO-A pathway","volume":"178","author":"Huang","year":"2023","journal-title":"Food Chem. Toxicol."},{"key":"B12","doi-asserted-by":"publisher","first-page":"173","DOI":"10.1016\/j.ijpharm.2015.10.057","article-title":"Double emulsion solvent evaporation techniques used for drug encapsulation","volume":"496","author":"Iqbal","year":"2015","journal-title":"Int. J. Pharm."},{"key":"B13","doi-asserted-by":"publisher","first-page":"3","DOI":"10.1186\/s40824-020-0184-8","article-title":"Emerging role of nanosuspensions in drug delivery systems","volume":"24","author":"Jacob","year":"2020","journal-title":"Biomater. Res."},{"key":"B14","doi-asserted-by":"publisher","first-page":"46","DOI":"10.1007\/s11095-019-2571-1","article-title":"Pharmacokinetics, tissue distribution and excretion of Ag2S quantum dots in mice and rats: the effects of injection dose, particle size and surface charge","volume":"36","author":"Javidi","year":"2019","journal-title":"Pharm. Res."},{"key":"B15","doi-asserted-by":"publisher","first-page":"375","DOI":"10.3390\/mi10060375","article-title":"Recent progress in microfluidic models of the blood-brain barrier","volume":"10","author":"Jiang","year":"2019","journal-title":"Micromachines(Basel)"},{"key":"B16","doi-asserted-by":"publisher","first-page":"288","DOI":"10.1016\/j.ijpharm.2018.07.009","article-title":"Characterization of a smart pH-cleavable PEG polymer towards the development of dual pH-sensitive liposomes","volume":"548","author":"Kanamala","year":"2018","journal-title":"Int. J. Pharm."},{"key":"B41","doi-asserted-by":"publisher","first-page":"631","DOI":"10.1016\/j.addr.2007.05.003","article-title":"Nanosizing\u2013oral formulation development and biopharmaceutical evaluation","volume":"59","author":"Kesisoglou","year":"2007","journal-title":"Adv. Drug Deliv. Rev."},{"key":"B17","doi-asserted-by":"publisher","first-page":"824","DOI":"10.1016\/j.drudis.2015.02.009","article-title":"Nanoparticle technology for treatment of Parkinson\u2019s disease: the role of surface phenomena in reaching the brain","volume":"20","author":"Leyva-G\u00f3mez","year":"2015","journal-title":"Drug Discov. Today."},{"key":"B18","doi-asserted-by":"publisher","first-page":"1545585","DOI":"10.3389\/fphar.2025.1545585","article-title":"NMN reverses D-galactose-induced neurodegeneration and enhances the intestinal barrier of mice by activating the Sirt1 pathway","volume":"16","author":"Lin","year":"2025","journal-title":"Front. Pharmacol."},{"key":"B39","doi-asserted-by":"publisher","first-page":"369","DOI":"10.1007\/s10534-018-0094-6","article-title":"Role of lactoferrin and its receptors on biliary epithelium","volume":"31","author":"Mancinelli","year":"2018","journal-title":"Biometals"},{"key":"B19","doi-asserted-by":"publisher","first-page":"1213","DOI":"10.1002\/jps.24322","article-title":"A review of the potential role of nano-enabled drug delivery technologies in amyotrophic lateral sclerosis: lessons learned from other neurodegenerative disorders","volume":"104","author":"Mazibuko","year":"2015","journal-title":"J. Pharm. Sci."},{"key":"B20","doi-asserted-by":"publisher","first-page":"115370","DOI":"10.1016\/j.colsurfb.2025.115370","article-title":"Frankincense-loaded lactoferrin-conjugated solid lipid nanoparticles for targeted brain delivery and neuroprotection in a scopolamine-induced Alzheimer\u2019s model","volume":"260","author":"Moazzam","year":"2026","journal-title":"Colloid. Surf. B"},{"key":"B21","doi-asserted-by":"publisher","first-page":"1137","DOI":"10.1023\/a:1019842024814","article-title":"Synthesis of pegylated immunonanoparticles","volume":"19","author":"Olivier","year":"2002","journal-title":"Pharm. Res."},{"key":"B22","doi-asserted-by":"publisher","first-page":"102585","DOI":"10.1016\/j.npep.2026.102585","article-title":"Targeting the brain through the nose: advances in polymeric nanoparticle delivery for schizophrenia","volume":"116","author":"Ponduri","year":"2026","journal-title":"Neuropeptides"},{"key":"B23","doi-asserted-by":"publisher","first-page":"3304","DOI":"10.1021\/nn300240p","article-title":"Receptor-mediated delivery of magnetic nanoparticles across the blood-brain barrier","volume":"6","author":"Qiao","year":"2012","journal-title":"ACS Nano"},{"key":"B24","doi-asserted-by":"publisher","first-page":"125","DOI":"10.3390\/ijms26010125","article-title":"Antioxidant potential of lactoferrin and its protective effect on health: an overview","volume":"26","author":"Rasc\u00f3n-Cruz","year":"2024","journal-title":"Int. J. Mol. Sci."},{"key":"B25","doi-asserted-by":"publisher","first-page":"532","DOI":"10.7535\/hbkd.2018yx06008","article-title":"Preparation and characterization of curcumin long-circulating liposomes","volume":"39","author":"Ren","year":"2018","journal-title":"J. Hebei Univ. Sci. Technol."},{"key":"B26","doi-asserted-by":"publisher","first-page":"3356","DOI":"10.3390\/nu13103356","article-title":"Lactoferrin protects against methamphetamine toxicity by modulating autophagy and mitochondrial status","volume":"13","author":"Ryskalin","year":"2021","journal-title":"Nutrients"},{"key":"B27","doi-asserted-by":"publisher","first-page":"104726","DOI":"10.1016\/j.chemphyslip.2019.01.004","article-title":"Effect of surface charge on the size-dependent cellular internalization of liposomes","volume":"224","author":"Sakai-Kato","year":"2019","journal-title":"Chem. Phys. Lipids"},{"key":"B28","first-page":"2004","article-title":"Lactoferrin-conjugated poly(ethylene glycol)-coated Fe3O4 nanoparticles","volume-title":"Molecular Imaging and Contrast Agent Database (MICAD)","author":"Shan","year":"2012"},{"key":"B29","doi-asserted-by":"publisher","first-page":"1788","DOI":"10.1080\/1061186X.2025.2529528","article-title":"A pioneer review on lactoferrin as versatile macromolecular ligand for targeting cancer: recent advances","volume":"33","author":"Sharma","year":"2025","journal-title":"J. Drug Target."},{"key":"B30","doi-asserted-by":"publisher","first-page":"20410","DOI":"10.1021\/acsami.7b03504","article-title":"In vitro study of receptor-mediated silica nanoparticles delivery across blood-brain barrier","volume":"9","author":"Song","year":"2017","journal-title":"ACS. Appl. Mater. Interfaces"},{"key":"B31","doi-asserted-by":"publisher","first-page":"753","DOI":"10.1007\/s00396-003-1015-x","article-title":"Effect of a PEG lipid (DSPE-PEG2000) and freeze-thawing process on phospholipid vesicle size and lamellarity","volume":"282","author":"Sriwongsitanont","year":"2004","journal-title":"Colloid poly. Sci."},{"key":"B40","doi-asserted-by":"publisher","first-page":"5757","DOI":"10.1021\/acsabm.5c00482","article-title":"Lactoferrin-anchored carboxymethyl pullulan-MgO nanocomposites for targeted delivery of trans-ferulic acid: physicochemical characterization, in vitro and ex vivo studies","volume":"8","author":"Sirvi","year":"2025","journal-title":"ACS Appl. Bio. Mater."},{"key":"B32","doi-asserted-by":"publisher","first-page":"105035","DOI":"10.1016\/j.nanoen.2020.105035","article-title":"Ultra-Stretchable, durable and conductive hydrogel with hybrid double network as high performance strain sensor and stretchable triboelectric nanogenerator","volume":"76","author":"Sun","year":"2020","journal-title":"Nano. Energy"},{"key":"B33","doi-asserted-by":"publisher","first-page":"114465","DOI":"10.1016\/j.jconrel.2025.114465","article-title":"Long-acting lipid-based nanomedicines: rethinking from structure-based rational design to in vivo fate evaluation","volume":"389","author":"Tang","year":"2024","journal-title":"J. Control. Release."},{"key":"B34","doi-asserted-by":"publisher","first-page":"11732","DOI":"10.3390\/app142411732","article-title":"Construction of nicotinamide mononucleotide-loaded liposomes and their in vitro transport across the blood\u2013brain barrier","volume":"14","author":"Wang","year":"2024","journal-title":"Appl. Sci."},{"key":"B35","doi-asserted-by":"publisher","first-page":"28351","DOI":"10.1021\/acsomega.5c03435","article-title":"PEGylating Ag2S semiconductor nanocrystals for pharmacokinetics tracking: insights from NIR luminescence imaging","volume":"10","author":"Zabala-Gutierrez","year":"2025","journal-title":"ACS Omega"},{"key":"B36","doi-asserted-by":"publisher","first-page":"1569","DOI":"10.1093\/jpp\/rgad090","article-title":"Hydroxyapatite-based nano-drug delivery system for nicotinamide mononucleotide (NMN): significantly enhancing NMN bioavailability and replenishing in vivo nicotinamide adenine dinucleotide (NAD+) levels","volume":"75","author":"Zhang","year":"2023","journal-title":"J. Pharm. Pharmacol."},{"key":"B37","doi-asserted-by":"publisher","first-page":"307","DOI":"10.7150\/ijms.80942","article-title":"Nicotinamide mononucleotides alleviated neurological impairment via anti-neuroinflammation in traumatic brain injury","volume":"20","author":"Zhu","year":"2023","journal-title":"Int. J. Med. Sci."},{"key":"B38","doi-asserted-by":"publisher","first-page":"3173","DOI":"10.1007\/s13346-024-01538-5","article-title":"Design of charge converting lipid nanoparticles via a microfluidic coating technique","volume":"14","author":"Z\u00f6ller","year":"2024","journal-title":"Drug Deliv. Transl. Res."}],"container-title":["Frontiers in Chemistry"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fchem.2026.1759167\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,29]],"date-time":"2026-06-29T12:05:34Z","timestamp":1782734734000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fchem.2026.1759167\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,6,17]]},"references-count":41,"alternative-id":["10.3389\/fchem.2026.1759167"],"URL":"https:\/\/doi.org\/10.3389\/fchem.2026.1759167","relation":{},"ISSN":["2296-2646"],"issn-type":[{"value":"2296-2646","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,6,17]]},"article-number":"1759167"}}