{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T15:47:20Z","timestamp":1792079240374,"version":"4.4.0"},"reference-count":34,"publisher":"American Chemical Society (ACS)","issue":"9","license":[{"start":{"date-parts":[[2026,8,13]],"date-time":"2026-08-13T00:00:00Z","timestamp":1786579200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01DK131190"],"award-info":[{"award-number":["R01DK131190"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R35GM152102"],"award-info":[{"award-number":["R35GM152102"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100007904","name":"Texas A and M University","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100007904","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,9,18]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Copper (Cu) is an essential trace element that serves as a cofactor for enzymes involved in diverse metabolic pathways and processes across multiple subcellular compartments. Mutations that cause systemic or subcellular Cu deficiency result in fatal pediatric disorders, including Menkes disease and related mitochondrial disorders. Treatment of these disorders requires pharmacological agents that can transport Cu across membranes; however, the only approved drug, Cu histidinate, shows limited efficacy. Using genetic models of Menkes disease, we recently demonstrated that the Cu ionophore elesclomol (ES) efficiently restores the activity of mitochondrial and cytosolic cuproenzymes, but its ability to metalate cuproenzymes within secretory compartments is low. To overcome this limitation, we investigated Cu nanoparticles (Cu-NPs) as a facile means of delivering Cu to multiple subcellular compartments simultaneously. Cu-NPs were synthesized by chemical reduction to produce spherical nanoparticles with an average size of 80 nm. Biophysical characterization of Cu-NPs revealed zero-valent Cu and a neutral zeta potential, compatible with biological interactions and in vivo circulation. In cellular models of Cu deficiency, Cu-NPs were shown to internalize via clathrin-mediated endocytosis and restore the activity of cuproenzymes in mitochondrial, cytosolic, and secretory compartments. Importantly, biomarkers of Cu toxicity were not activated under these conditions, indicating a favorable therapeutic index. Overall, these findings highlight Cu-NPs as versatile Cu delivery agents with therapeutic potential for Cu deficiency disorders.<\/jats:p>","DOI":"10.1021\/acschembio.6c00564","type":"journal-article","created":{"date-parts":[[2026,8,13]],"date-time":"2026-08-13T09:02:25Z","timestamp":1786611745000},"page":"2441-2450","source":"Crossref","is-referenced-by-count":0,"title":["Copper Nanoparticles Enable Multi-Compartment Cuproenzyme Metalation in Cellular Models of Copper Deficiency"],"prefix":"10.1021","volume":"21","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7536-9991","authenticated-orcid":true,"given":"Harman","family":"Kaur","sequence":"first","affiliation":[{"name":"Texas A&M University , , , ,","place":["College Station, Texas, United States, 77843"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1175-2895","authenticated-orcid":true,"given":"John","family":"Soukar","sequence":"additional","affiliation":[{"name":"Texas A&M University , , , ,","place":["College Station, Texas, United States, 77843"]},{"name":"Texas A&M University , , , ,","place":["College Station, Texas, United States, 77843"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nikita","family":"Gudekar","sequence":"additional","affiliation":[{"name":"University of Missouri , , , ,","place":["Columbia, Missouri, United States, 65211"]},{"name":"University of Missouri , , , ,","place":["Columbia, Missouri, United States, 65211"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vinit C.","family":"Shanbhag","sequence":"additional","affiliation":[{"name":"University of Missouri , , , ,","place":["Columbia, Missouri, United States, 65211"]},{"name":"University of Missouri , , , ,","place":["Columbia, Missouri, United States, 65211"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael J.","family":"Petris","sequence":"additional","affiliation":[{"name":"University of Missouri , , , ,","place":["Columbia, Missouri, United States, 65211"]},{"name":"University of Missouri , , , ,","place":["Columbia, Missouri, United States, 65211"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0284-0201","authenticated-orcid":true,"given":"Akhilesh K.","family":"Gaharwar","sequence":"additional","affiliation":[{"name":"Texas A&M University , , , ,","place":["College Station, Texas, United States, 77843"]},{"name":"Texas A&M University , , , ,","place":["College Station, Texas, United States, 77843"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9920-2563","authenticated-orcid":true,"given":"Vishal M.","family":"Gohil","sequence":"additional","affiliation":[{"name":"Texas A&M University , , , ,","place":["College Station, Texas, United States, 77843"]},{"name":"Texas A&M University , , , ,","place":["College Station, Texas, United States, 77843"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,8,13]]},"reference":[{"issue":"1","key":"2026101511064405900_cit1","doi-asserted-by":"publisher","first-page":"21","DOI":"10.1016\/j.tem.2022.11.001","article-title":"Mitochondrial copper in human genetic disorders","volume":"34","author":"Garza","year":"2023","journal-title":"Trends Endocrinol. Metab."},{"issue":"5","key":"2026101511064405900_cit2","doi-asserted-by":"publisher","first-page":"511","DOI":"10.1038\/ejhg.2009.187","article-title":"Menkes disease","volume":"18","author":"Tumer","year":"2010","journal-title":"Eur. J. Hum. Genet."},{"key":"2026101511064405900_cit3","first-page":"1745","volume-title":"Handbook of Clinical Neurology","author":"Kaler","year":"2013"},{"issue":"5","key":"2026101511064405900_cit4","doi-asserted-by":"publisher","first-page":"1104","DOI":"10.1016\/S0002-9297(07)62940-1","article-title":"Mutations of the SCO1 gene in mitochondrial cytochrome c oxidase deficiency with neonatal-onset hepatic failure and encephalopathy","volume":"67","author":"Valnot","year":"2000","journal-title":"Am. J. Hum. Genet."},{"issue":"13","key":"2026101511064405900_cit5","doi-asserted-by":"publisher","first-page":"3596","DOI":"10.1093\/hmg\/ddu069","article-title":"Copper supplementation restores cytochrome c oxidase assembly defect in a mitochondrial disease model of COA6 deficiency","volume":"23","author":"Ghosh","year":"2014","journal-title":"Hum. Mol. Genet."},{"issue":"3","key":"2026101511064405900_cit6","doi-asserted-by":"publisher","first-page":"333","DOI":"10.1038\/15513","article-title":"Fatal infantile cardioencephalomyopathy with COX deficiency and mutations in SCO2, a COX assembly gene","volume":"23","author":"Papadopoulou","year":"1999","journal-title":"Nat. Genet."},{"key":"2026101511064405900_cit7","doi-asserted-by":"publisher","first-page":"59","DOI":"10.1007\/8904_2014_364","article-title":"Pathologic Variants of the Mitochondrial Phosphate Carrier SLC25A3: Two New Patients and Expansion of the Cardiomyopathy\/Skeletal Myopathy Phenotype With and Without Lactic Acidosis","volume":"19","author":"Bhoj","year":"2015","journal-title":"JIMD Rep."},{"issue":"24","key":"2026101511064405900_cit8","doi-asserted-by":"publisher","first-page":"4121","DOI":"10.1093\/hmg\/ddac156","article-title":"Newly identified disorder of copper metabolism caused by variants in CTR1, a high-affinity copper transporter","volume":"31","author":"Batzios","year":"2022","journal-title":"Hum. Mol. Genet."},{"issue":"5","key":"2026101511064405900_cit9","doi-asserted-by":"publisher","first-page":"585","DOI":"10.1111\/cge.14289","article-title":"Fatal congenital copper transport defect caused by a homozygous likely pathogenic variant of SLC31A1","volume":"103","author":"Dame","year":"2023","journal-title":"Clin. Genet."},{"issue":"5","key":"2026101511064405900_cit10","doi-asserted-by":"publisher","first-page":"828","DOI":"10.1016\/s0022-3476(05)80870-4","article-title":"Copper-histidine therapy for Menkes disease","volume":"123","author":"Sarkar","year":"1993","journal-title":"J. Pediatr."},{"issue":"6","key":"2026101511064405900_cit11","doi-asserted-by":"publisher","first-page":"921","DOI":"10.1002\/ana.410380613","article-title":"Early copper therapy in classic Menkes disease patients with a novel splicing mutation","volume":"38","author":"Kaler","year":"1995","journal-title":"Ann. Neurol."},{"issue":"6","key":"2026101511064405900_cit12","doi-asserted-by":"publisher","first-page":"605","DOI":"10.1056\/NEJMoa070613","article-title":"Neonatal diagnosis and treatment of Menkes disease","volume":"358","author":"Kaler","year":"2008","journal-title":"N. Engl. J. Med."},{"key":"2026101511064405900_cit13"},{"issue":"12","key":"2026101511064405900_cit14","doi-asserted-by":"publisher","first-page":"2114","DOI":"10.1038\/mt.2011.143","article-title":"ATP7A gene addition to the choroid plexus results in long-term rescue of the lethal copper transport defect in a Menkes disease mouse model","volume":"19","author":"Donsante","year":"2011","journal-title":"Mol. Ther."},{"issue":"32","key":"2026101511064405900_cit15","doi-asserted-by":"publisher","first-page":"8161","DOI":"10.1073\/pnas.1806296115","article-title":"Elesclomol restores mitochondrial function in genetic models of copper deficiency","volume":"115","author":"Soma","year":"2018","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"issue":"6491","key":"2026101511064405900_cit16","doi-asserted-by":"publisher","first-page":"620","DOI":"10.1126\/science.aaz8899","article-title":"Elesclomol alleviates Menkes pathology and mortality by escorting Cu to cuproenzymes in mice","volume":"368","author":"Guthrie","year":"2020","journal-title":"Science"},{"issue":"1","key":"2026101511064405900_cit17","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1080\/13543784.2021.1840550","article-title":"Repurposing elesclomol, an investigational drug for the treatment of copper metabolism disorders","volume":"30","author":"Gohil","year":"2021","journal-title":"Expert Opin. Investig. Drugs"},{"issue":"7","key":"2026101511064405900_cit18","doi-asserted-by":"publisher","DOI":"10.1016\/j.jbc.2022.102139","article-title":"Elesclomol elevates cellular and mitochondrial iron levels by delivering copper to the iron import machinery","volume":"298","author":"Garza","year":"2022","journal-title":"J. Biol. Chem."},{"issue":"19","key":"2026101511064405900_cit19","doi-asserted-by":"publisher","DOI":"10.1172\/JCI193107","article-title":"Elesclomol-copper therapy improves neurodevelopment in two children with Menkes disease","volume":"135","author":"Godoy-Molina","year":"2025","journal-title":"J. Clin. Invest."},{"key":"2026101511064405900_cit20","doi-asserted-by":"publisher","first-page":"68","DOI":"10.1016\/j.addr.2019.04.008","article-title":"Concepts of nanoparticle cellular uptake, intracellular trafficking, and kinetics in nanomedicine","volume":"143","author":"Donahue","year":"2019","journal-title":"Adv. Drug Delivery Rev."},{"issue":"1","key":"2026101511064405900_cit21","doi-asserted-by":"publisher","first-page":"21","DOI":"10.1007\/s40089-015-0163-6","article-title":"A chemical reduction approach to the synthesis of copper nanoparticles","volume":"6","author":"Khan","year":"2016","journal-title":"Int. Nano Lett."},{"issue":"1","key":"2026101511064405900_cit22","doi-asserted-by":"publisher","first-page":"0378","DOI":"10.1016\/j.ijpharm.2005.10.010","article-title":"Opsonization, biodistribution and pharmacokinetics of polymeric nanoparticles","volume":"307","author":"Owens","year":"2006","journal-title":"Int. J. Pharm."},{"issue":"13","key":"2026101511064405900_cit23","doi-asserted-by":"publisher","first-page":"1325","DOI":"10.1002\/sia.6239","article-title":"Advanced analysis of copper X-ray photoelectron spectra","volume":"49","author":"Biesinger","year":"2017","journal-title":"Surf. Interface Anal."},{"key":"2026101511064405900_cit24","doi-asserted-by":"publisher","DOI":"10.1016\/j.mtcomm.2020.101692","article-title":"Cellular uptake and retention of nanoparticles: Insights on particle properties and interaction with cellular components","volume":"25","author":"Augustine","year":"2020","journal-title":"Mater. Today Commun."},{"issue":"24","key":"2026101511064405900_cit25","doi-asserted-by":"publisher","first-page":"13329","DOI":"10.1073\/pnas.1914345117","article-title":"Photothermal modulation of human stem cells using light-responsive 2D nanomaterials","volume":"117","author":"Carrow","year":"2020","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"issue":"11","key":"2026101511064405900_cit26","doi-asserted-by":"publisher","first-page":"9639","DOI":"10.1074\/jbc.M209455200","article-title":"Copper-stimulated endocytosis and degradation of the human copper transporter, hCtr1","volume":"278","author":"Petris","year":"2003","journal-title":"J. Biol. Chem."},{"issue":"6586","key":"2026101511064405900_cit27","doi-asserted-by":"publisher","first-page":"1254","DOI":"10.1126\/science.abf0529","article-title":"Copper induces cell death by targeting lipoylated TCA cycle proteins","volume":"375","author":"Tsvetkov","year":"2022","journal-title":"Science"},{"issue":"4","key":"2026101511064405900_cit28","doi-asserted-by":"publisher","first-page":"735","DOI":"10.2147\/IJN.S2.4.735","article-title":"PEGylation of nanoparticles improves their cytoplasmic transport","volume":"2","author":"Suh","year":"2007","journal-title":"Int. J. Nanomed."},{"issue":"34","key":"2026101511064405900_cit29","doi-asserted-by":"publisher","first-page":"40267","DOI":"10.1021\/acsami.1c09366","article-title":"Journey of Poly(ethylene Glycol) in Living Cells","volume":"13","author":"Yang","year":"2021","journal-title":"ACS Appl. Mater. Interfaces"},{"key":"2026101511064405900_cit30","doi-asserted-by":"publisher","first-page":"786","DOI":"10.1038\/nrm2258","article-title":"Melanosomes--dark organelles enlighten endosomal membrane transport","volume":"10","author":"Raposo","year":"2007","journal-title":"Nat. Rev. Mol. Cell Biol."},{"issue":"2","key":"2026101511064405900_cit31","doi-asserted-by":"publisher","first-page":"247","DOI":"10.1083\/jcb.200907122","article-title":"AP-1 and KIF13A coordinate endosomal sorting and positioning during melanosome biogenesis","volume":"187","author":"Delevoye","year":"2009","journal-title":"J. Cell Biol."},{"issue":"7208","key":"2026101511064405900_cit32","doi-asserted-by":"publisher","first-page":"1142","DOI":"10.1038\/nature07163","article-title":"Cell-specific ATP7A transport sustains copper-dependent tyrosinase activity in melanosomes","volume":"454","author":"Setty","year":"2008","journal-title":"Nature"},{"issue":"19","key":"2026101511064405900_cit33","doi-asserted-by":"publisher","first-page":"2845","DOI":"10.1093\/hmg\/9.19.2845","article-title":"The Menkes copper transporter is required for the activation of tyrosinase","volume":"9","author":"Petris","year":"2000","journal-title":"Hum. Mol. Genet."},{"key":"2026101511064405900_cit34","doi-asserted-by":"publisher","first-page":"93","DOI":"10.1016\/s0076-6879(84)05013-8","article-title":"Superoxide dismutase assays","volume":"105","author":"Flohe","year":"1984","journal-title":"Methods Enzymol."}],"container-title":["ACS Chemical Biology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pubs.acs.org\/doi\/pdf\/10.1021\/acschembio.6c00564","content-type":"application\/pdf","content-version":"vor","intended-application":"unspecified"},{"URL":"https:\/\/pubs.acs.org\/acbcct\/article-pdf\/21\/9\/2441\/66522107\/cb-2026-00564e.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/pubs.acs.org\/acbcct\/article-pdf\/21\/9\/2441\/66522107\/cb-2026-00564e.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T15:17:12Z","timestamp":1792077432000},"score":1,"resource":{"primary":{"URL":"https:\/\/pubs.acs.org\/acbcct\/article\/21\/9\/2441\/5254102\/Copper-Nanoparticles-Enable-Multi-Compartment"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,13]]},"references-count":34,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2026,8,13]]},"published-print":{"date-parts":[[2026,9,18]]}},"URL":"https:\/\/doi.org\/10.1021\/acschembio.6c00564","relation":{},"ISSN":["1554-8929","1554-8937"],"issn-type":[{"value":"1554-8929","type":"print"},{"value":"1554-8937","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,13]]}}}