{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T20:01:41Z","timestamp":1790193701649,"version":"4.1.0"},"reference-count":45,"publisher":"American Chemical Society (ACS)","issue":"8","license":[{"start":{"date-parts":[[2015,6,20]],"date-time":"2015-06-20T00:00:00Z","timestamp":1434758400000},"content-version":"vor","delay-in-days":365,"URL":"https:\/\/pubs.acs.org\/page\/policy\/authorchoice_termsofuse.html"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["HL098416"],"award-info":[{"award-number":["HL098416"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2014,8,4]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Drugs often use endocytosis to achieve intracellular delivery, either by passive uptake from the extracellular fluid or by active targeting of cell surface features such as endocytic receptors. An example is enzyme replacement therapy, a clinically practiced treatment for several lysosomal storage diseases where glycosylated recombinant enzymes naturally target the mannose-6-phosphate receptor and are internalized by clathrin mediated endocytosis (CME). However, lysosomal substrate accumulation, a hallmark of these diseases, has been indirectly linked to aberrant endocytic activity. These effects are poorly understood, creating an obstacle to therapeutic efficiency. Here we explored endocytic activity in fibroblasts from patients with type A Niemann\u2013Pick disease, a lysosomal storage disease characterized by acid sphingomyelinase (ASM) deficiency. The uptake of fluid phase markers and clathrin-associated ligands, formation of endocytic structures, and recruitment of intracellular clathrin to ligand binding sites were all altered, demonstrating aberrant CME in these cells. Model polymer nanocarriers targeted to intercellular adhesion molecule-1 (ICAM-1), which are internalized by a clathrin-independent route, enhanced the intracellular delivery of recombinant ASM more than 10-fold compared to free enzyme. This strategy reduced substrate accumulation and restored clathrin endocytic activity to wild-type levels. There appears to be a relationship between lysosomal storage and diminished CME, and bypassing this pathway by targeting ICAM-1 may enhance future therapies for lysosomal storage diseases.<\/jats:p>","DOI":"10.1021\/mp500241y","type":"journal-article","created":{"date-parts":[[2014,6,20]],"date-time":"2014-06-20T09:22:12Z","timestamp":1403256132000},"page":"2887-2895","source":"Crossref","is-referenced-by-count":29,"title":["Clathrin-Mediated Endocytosis Is Impaired in Type\nA\u2013B Niemann\u2013Pick Disease Model Cells and Can Be Restored\nby ICAM-1-Mediated Enzyme Replacement"],"prefix":"10.1021","volume":"11","author":[{"given":"Jeff","family":"Rappaport","sequence":"first","affiliation":[{"name":"University of Maryland , , , ,","place":["College Park, Maryland, United States, 20742-4450"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carmen","family":"Garnacho","sequence":"additional","affiliation":[{"name":"University of Seville School of Medicine , , ,","place":["Seville, Spain, 41009"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Silvia","family":"Muro","sequence":"additional","affiliation":[{"name":"University of Maryland , , , ,","place":["College Park, Maryland, United States, 20742-4450"]},{"name":"University of Maryland , , 5115 Plant Sciences Building , , ,","place":["College Park, Maryland, United States, 20742-4450"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2014,6,20]]},"reference":[{"key":"2026090202574431800_cit1","doi-asserted-by":"crossref","first-page":"575","DOI":"10.1146\/annurev.cellbio.12.1.575","article-title":"Endocytosis\nand Molecular Sorting","volume":"12","author":"Mellman","year":"1996","journal-title":"Annu. Rev. Cell. Dev.\nBiol."},{"key":"2026090202574431800_cit2","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1038\/nature01451","article-title":"Regulated Portals\nof Entry into the Cell","volume":"422","author":"Conner","year":"2003","journal-title":"Nature"},{"key":"2026090202574431800_cit3","doi-asserted-by":"crossref","first-page":"215","DOI":"10.1126\/science.285.5425.215","article-title":"The Structural Era\nof Endocytosis","volume":"285","author":"Marsh","year":"1999","journal-title":"Science"},{"key":"2026090202574431800_cit4","doi-asserted-by":"crossref","first-page":"1301","DOI":"10.1089\/ars.2008.2397","article-title":"Vesicle\nFormation and Endocytosis: Function, Machinery, Mechanisms, and Modeling","volume":"11","author":"Parkar","year":"2009","journal-title":"Antioxid. Redox Signaling"},{"key":"2026090202574431800_cit5","doi-asserted-by":"crossref","first-page":"517","DOI":"10.1038\/nrm3151","article-title":"Molecular Mechanism and Physiological Functions of\nClathrin-Mediated Endocytosis","volume":"12","author":"McMahon","year":"2011","journal-title":"Nature Rev. Mol.\nCell. Biol."},{"key":"2026090202574431800_cit6","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1042\/bj20031000","article-title":"Clathrin-Dependent\nEndocytosis","volume":"377","author":"Mousavi","year":"2004","journal-title":"Biochem. J."},{"key":"2026090202574431800_cit7","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1016\/j.jconrel.2012.05.052","article-title":"Challenges\nin Design and Characterization of Ligand-Targeted Drug Delivery Systems","volume":"164","author":"Muro","year":"2012","journal-title":"J. Controlled Release"},{"key":"2026090202574431800_cit8","doi-asserted-by":"crossref","first-page":"554","DOI":"10.1038\/nrm1423","article-title":"The Cell Biology of Lysosomal Storage Disorders","volume":"5","author":"Futerman","year":"2004","journal-title":"Nature Rev. Mol. Cell. Biol."},{"key":"2026090202574431800_cit9","doi-asserted-by":"crossref","first-page":"954","DOI":"10.1038\/nrg963","article-title":"Enzyme Replacement and Enhancement Therapies: Lessons\nfrom Lysosomal Disorders","volume":"3","author":"Desnick","year":"2002","journal-title":"Nature Rev. Genet."},{"key":"2026090202574431800_cit10","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1007\/s00439-006-0280-4","article-title":"New Therapeutic\nOptions for Lysosomal Storage Disorders: Enzyme Replacement, Small\nMolecules and Gene Therapy","volume":"121","author":"Beck","year":"2007","journal-title":"Hum. Genet."},{"key":"2026090202574431800_cit11","first-page":"77","article-title":"The Uptake\nof Enzymes into Lysosomes: an Overview","volume":"16","author":"Neufeld","year":"1980","journal-title":"Birth\nDefects Orig. Artic. Ser."},{"key":"2026090202574431800_cit12","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1007\/s13346-012-0072-4","article-title":"Strategies\nfor Delivery of Therapeutics Into the Central Nervous System for Treatment\nof Lysosomal Storage Disorders","volume":"2","author":"Muro","year":"2012","journal-title":"Drug Delivery\nTransl. Res."},{"key":"2026090202574431800_cit13","doi-asserted-by":"crossref","first-page":"459","DOI":"10.1016\/S0962-8924(00)01847-X","article-title":"Jamming the\nEndosomal System: Lipid Rafts and Lysosomal\nStorage Diseases","volume":"10","author":"Simons","year":"2000","journal-title":"Trends Cell. Biol."},{"key":"2026090202574431800_cit14","doi-asserted-by":"crossref","first-page":"3607","DOI":"10.1038\/emboj.2010.237","article-title":"Lysosomal Fusion and\nSNARE Function are Impaired by Cholesterol Accumulation in Lysosomal\nStorage Disorders","volume":"29","author":"Fraldi","year":"2010","journal-title":"EMBO J."},{"key":"2026090202574431800_cit15","doi-asserted-by":"crossref","first-page":"684","DOI":"10.1016\/j.bbamcr.2008.12.001","article-title":"Lysosomal Disorders: from Storage\nto Cellular Damage","volume":"1793","author":"Ballabio","year":"2009","journal-title":"Biochim. Biophys. Acta"},{"key":"2026090202574431800_cit16","doi-asserted-by":"crossref","first-page":"700","DOI":"10.1002\/ana.20807","article-title":"Dysfunction\nof Endocytic and Autophagic Pathways in a Lysosomal Storage Disease","volume":"59","author":"Fukuda","year":"2006","journal-title":"Ann. Neurol."},{"key":"2026090202574431800_cit17","doi-asserted-by":"crossref","first-page":"605","DOI":"10.1016\/S0962-8924(02)02399-1","article-title":"Endocytosis and Sorting of Glycosphingolipids in Sphingolipid\nStorage Disease","volume":"12","author":"Marks","year":"2002","journal-title":"Trends Cell. Biol."},{"key":"2026090202574431800_cit18","doi-asserted-by":"crossref","first-page":"705","DOI":"10.1007\/s10719-008-9191-z","article-title":"Cholesterol\nRegulation of Rab-Mediated Sphingolipid\nEndocytosis","volume":"26","author":"Takahashi","year":"2009","journal-title":"Glycoconjugate J."},{"key":"2026090202574431800_cit19","doi-asserted-by":"crossref","first-page":"1526","DOI":"10.1074\/jbc.M309465200","article-title":"Mannose\n6-Phosphate Receptor-Mediated Uptake is Defective\nin Acid Sphingomyelinase-Deficient Macrophages: Implications for Niemann\u2013Pick\nDisease Enzyme Replacement Therapy","volume":"279","author":"Dhami","year":"2004","journal-title":"J. Biol.\nChem."},{"key":"2026090202574431800_cit20","doi-asserted-by":"crossref","first-page":"386","DOI":"10.1038\/14084","article-title":"Cholesterol Modulates\nMembrane Traffic\nAlong the Endocytic Pathway in Sphingolipid-Storage Diseases","volume":"1","author":"Puri","year":"1999","journal-title":"Nature Cell Biol."},{"key":"2026090202574431800_cit21","doi-asserted-by":"crossref","first-page":"731","DOI":"10.1016\/j.nano.2011.08.014","article-title":"Enhanced Delivery of\n\u03b1-Glucosidase for Pompe Disease by ICAM-1-Targeted Nanocarriers:\nComparative Performance of a Strategy for Three Distinct Lysosomal\nStorage Disorders","volume":"8","author":"Hsu","year":"2012","journal-title":"Nanomedicine"},{"key":"2026090202574431800_cit22","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1016\/j.ymthe.2005.07.687","article-title":"Lysosomal Enzyme Delivery by ICAM-1-Targeted\nNanocarriers Bypassing Glycosylation- and Clathrin-Dependent Endocytosis","volume":"13","author":"Muro","year":"2006","journal-title":"Mol. Ther."},{"key":"2026090202574431800_cit23","doi-asserted-by":"crossref","first-page":"1599","DOI":"10.1242\/jcs.00367","article-title":"A Novel Endocytic Pathway Induced\nby Clustering Endothelial ICAM-1 or PECAM-1","volume":"116","author":"Muro","year":"2003","journal-title":"J. Cell Sci."},{"key":"2026090202574431800_cit24","doi-asserted-by":"crossref","first-page":"400","DOI":"10.1124\/jpet.107.133298","article-title":"Delivery of Acid Sphingomyelinase\nin Normal and Niemann\u2013Pick Disease Mice Using Intercellular\nAdhesion Molecule-1-Targeted Polymer Nanocarriers","volume":"325","author":"Garnacho","year":"2008","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"2026090202574431800_cit25","doi-asserted-by":"crossref","first-page":"323","DOI":"10.1016\/j.jconrel.2010.10.031","article-title":"Enhanced Endothelial\nDelivery and Biochemical Effects of \u03b1-Galactosidase by ICAM-1-Targeted\nNanocarriers for Fabry Disease","volume":"149","author":"Hsu","year":"2011","journal-title":"J. Controlled\nRelease"},{"key":"2026090202574431800_cit26","doi-asserted-by":"crossref","first-page":"467","DOI":"10.1007\/s10545-012-9534-6","article-title":"Comparative Binding, Endocytosis, and Biodistribution of Antibodies\nand Antibody-Coated Carriers for Targeted Delivery of Lysosomal Enzymes\nto ICAM-1 versus Transferrin Receptor","volume":"36","author":"Papademetriou","year":"2013","journal-title":"J. Inherit.\nMetab. Dis."},{"key":"2026090202574431800_cit27","doi-asserted-by":"crossref","first-page":"1058","DOI":"10.1017\/CBO9780511546198.118","article-title":"Intercellular\nAdhesion Molecule-1 and Vascular Cell Adhesion Molecule-1","volume-title":"Endothelial Biomedicine","author":"Muro","year":"2007","edition":"1st"},{"key":"2026090202574431800_cit28","doi-asserted-by":"crossref","first-page":"1450","DOI":"10.1038\/mt.2008.127","article-title":"Control of Endothelial Targeting\nand Intracellular\nDelivery of Therapeutic Enzymes by Modulating the Size and Shape of\nICAM-1-Targeted Carriers","volume":"16","author":"Muro","year":"2008","journal-title":"Mol. Ther."},{"key":"2026090202574431800_cit29","doi-asserted-by":"crossref","first-page":"1855","DOI":"10.1007\/s11095-013-1289-8","article-title":"Specific Binding, Uptake, and Transport\nof ICAM-1-Targeted Nanocarriers Across Endothelial and Subendothelial\nComponents of the Blood\u2013Brain Barrier","volume":"31","author":"Hsu","year":"2014","journal-title":"Pharm. Res."},{"key":"2026090202574431800_cit30","first-page":"3589","article-title":"Niemann\u2013Pick\ndisease types A and B: Acid Sphingomyelinase Deficiencies","volume-title":"The Metabolic and Molecular Bases of Inherited Disease","author":"Schuchman","year":"2000","edition":"8th"},{"key":"2026090202574431800_cit31","doi-asserted-by":"crossref","first-page":"251","DOI":"10.1016\/S0167-4838(99)00069-2","article-title":"Characterization\nof Human Acid Sphingomyelinase Purified\nfrom the Media of Overexpressing Chinese Hamster Ovary Cells","volume":"1432","author":"He","year":"1999","journal-title":"Biochim. Biophys. Acta"},{"key":"2026090202574431800_cit32","doi-asserted-by":"crossref","first-page":"1161","DOI":"10.1124\/jpet.105.098970","article-title":"Endothelial Targeting of High-Affinity\nMultivalent Polymer Nanocarriers Directed to Intercellular Adhesion\nMolecule 1","volume":"317","author":"Muro","year":"2006","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"2026090202574431800_cit33","first-page":"21","article-title":"Characterization\nof Endothelial Internalization and Targeting of Antibody\u2013Enzyme\nConjugates in Cell Cultures and in Laboratory Animals","volume-title":"Methods in Molecular Biology","author":"Muro","year":"2004","edition":"1st"},{"key":"2026090202574431800_cit34","doi-asserted-by":"crossref","first-page":"748","DOI":"10.1016\/j.addr.2007.06.008","article-title":"Endocytic Mechanisms for Targeted\nDrug Delivery","volume":"59","author":"Bareford","year":"2007","journal-title":"Adv. Drug Delivery Rev."},{"key":"2026090202574431800_cit35","doi-asserted-by":"crossref","first-page":"857","DOI":"10.1146\/annurev.biochem.78.081307.110540","article-title":"Mechanisms of Endocytosis","volume":"78","author":"Doherty","year":"2009","journal-title":"Annu.\nRev. Biochem."},{"key":"2026090202574431800_cit36","doi-asserted-by":"crossref","first-page":"35283","DOI":"10.1074\/jbc.M111.267930","article-title":"Lysosomal\nStorage Causes Cellular Dysfunction in Mucolipidosis II Skin Fibroblasts","volume":"286","author":"Otomo","year":"2011","journal-title":"J. Biol. Chem."},{"key":"2026090202574431800_cit37","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1186\/1755-8417-1-6","article-title":"Abnormal Mannose-6-Phosphate Receptor\nTrafficking Impairs Recombinant alpha-Glucosidase Uptake in Pompe\nDisease Fibroblasts","volume":"1","author":"Cardone","year":"2008","journal-title":"Pathogenetics"},{"key":"2026090202574431800_cit38","doi-asserted-by":"crossref","first-page":"561","DOI":"10.1124\/pr.54.4.561","article-title":"Targeted Drug Delivery via the Transferrin\nReceptor-Mediated Endocytosis Pathway","volume":"54","author":"Qian","year":"2002","journal-title":"Pharmacol.\nRev."},{"key":"2026090202574431800_cit39","doi-asserted-by":"crossref","first-page":"1801","DOI":"10.1083\/jcb.135.6.1801","article-title":"AP-2-Containing Clathrin\nCoats Assemble on Mature Lysosomes","volume":"135","author":"Traub","year":"1996","journal-title":"J. Cell\nBiol."},{"key":"2026090202574431800_cit40","doi-asserted-by":"crossref","first-page":"924","DOI":"10.1038\/ncb2557","article-title":"Clathrin and Phosphatidylinositol-4,5-bisphosphate\nRegulate Autophagic Lysosome Reformation","volume":"14","author":"Rong","year":"2012","journal-title":"Nature\nCell Biol."},{"key":"2026090202574431800_cit41","doi-asserted-by":"crossref","first-page":"719","DOI":"10.4161\/auto.19469","article-title":"Autophagy\nin Lysosomal Storage Disorders","volume":"8","author":"Lieberman","year":"2012","journal-title":"Autophagy"},{"key":"2026090202574431800_cit42","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1515\/BC.2009.009","article-title":"Mannose 6-Phosphate\nReceptor-Dependent Endocytosis\nof Lysosomal Enzymes is Increased in Sulfatide-Storing Kidney Cells","volume":"390","author":"Klein","year":"2009","journal-title":"Biol. Chem."},{"key":"2026090202574431800_cit43","doi-asserted-by":"crossref","first-page":"C1339","DOI":"10.1152\/ajpcell.00099.2003","article-title":"Slow Intracellular Trafficking of Catalase Nanoparticles Targeted\nto ICAM-1 Protects Endothelial Cells from Oxidative Stress","volume":"285","author":"Muro","year":"2003","journal-title":"Am. J. Physiol.: Cell. Physiol."},{"key":"2026090202574431800_cit44","doi-asserted-by":"crossref","first-page":"17002","DOI":"10.1016\/S0021-9258(18)45483-X","article-title":"Low Density Lipoprotein\n(LDL)-Mediated Suppression\nof Cholesterol Synthesis and LDL Uptake is Defective in Niemann\u2013Pick\ntype C Fibroblasts","volume":"262","author":"Liscum","year":"1987","journal-title":"J. Biol. Chem."},{"key":"2026090202574431800_cit45","doi-asserted-by":"crossref","first-page":"778","DOI":"10.1091\/mbc.e09-01-0005","article-title":"Glycolipid Trafficking in Drosophila\nUndergoes Pathway Switching in Response to Aberrant Cholesterol Levels","volume":"21","author":"Hortsch","year":"2010","journal-title":"Mol. Biol. Cell"}],"container-title":["Molecular Pharmaceutics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pubs.acs.org\/doi\/pdf\/10.1021\/mp500241y","content-type":"application\/pdf","content-version":"vor","intended-application":"unspecified"},{"URL":"https:\/\/pubs.acs.org\/mpohbp\/article-pdf\/11\/8\/2887\/14376584\/mp500241y.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/pubs.acs.org\/mpohbp\/article-pdf\/11\/8\/2887\/14376584\/mp500241y.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,2]],"date-time":"2026-09-02T06:57:54Z","timestamp":1788332274000},"score":1,"resource":{"primary":{"URL":"https:\/\/pubs.acs.org\/mpohbp\/article\/11\/8\/2887\/1379898\/Clathrin-Mediated-Endocytosis-Is-Impaired-in-Type"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2014,6,20]]},"references-count":45,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2014,6,20]]},"published-print":{"date-parts":[[2014,8,4]]}},"URL":"https:\/\/doi.org\/10.1021\/mp500241y","relation":{},"ISSN":["1543-8384","1543-8392"],"issn-type":[{"value":"1543-8384","type":"print"},{"value":"1543-8392","type":"electronic"}],"subject":[],"published":{"date-parts":[[2014,6,20]]}}}