{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,9,15]],"date-time":"2026-09-15T17:06:39Z","timestamp":1789491999346,"version":"build-2803163510"},"posted":{"date-parts":[[2026,9,10]]},"group-title":"Cell Biology","reference-count":44,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T00:00:00Z","timestamp":1788998400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"name":"Takeda Pharmaceuticals","award":["IIR-USA-001523"],"award-info":[{"award-number":["IIR-USA-001523"]}]},{"award":["S10 OD021758-01A1"],"award-info":[{"award-number":["S10 OD021758-01A1"]}],"id":[{"id":"https:\/\/ror.org\/001d55x84","id-type":"ROR","asserted-by":"publisher"}]},{"award":["S10 OD030250-01A1"],"award-info":[{"award-number":["S10 OD030250-01A1"]}],"id":[{"id":"https:\/\/ror.org\/001d55x84","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,9,10]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                <jats:p>Mucopolysaccharidosis Type II (MPS-II) is a rare X-linked lysosomal storage disorder, characterized by deficiency of the lysosomal hydrolase iduronate 2-sulphatase (IDS). Cardiac impairments contribute to mortality in patients. Enzyme replacement therapy (ERT) with Idursulfase is a promising treatment for the cardiac dysfunction. We compared the proteome changes following intravenous (IV) with and without adjunct nebulized ERT in IDS-KO mice. Male mice were assigned to 4 groups: 1) WT IV + nebulized saline (WT; n=8); 2) IDS-KO IV + nebulized saline (KO; n=5); 3) IDS-KO IV Idursulfase (1 mg\/kg; KO-IV, n=5); 4) IDS-KO IV (1 mg\/kg) + nebulized Idursulfase (0.33 mg\/mouse; KO-NEB, n=5). Treatments were administered once a week starting at 8 weeks of age and the heart was harvested 12 weeks post-ERT. Mouse heart samples were prepared for global proteomics measurements with Nano-liquid chromatography tandem mass spectrometry (n=3\/group; Nano-LC\/MS\/MS). Global limma moderated F-test analysis identified 928 differently abundant proteins across the four groups. Pairwise Euclidean distances from the IDS-KO were significantly greater for the KO- NEB vs KO-IV group (47.5 \u00b1 3.7 vs 40.8 \u00b1 1.1; p &lt; 0.001), showing that adjunct nebulization elicited a more profound proteomic shift than IV alone. The mean z-score compartment analysis revealed that the subcellular compartment protein profile of KO-NEB shifted towards the WT profile, whereas this pattern was less evident in KO-IV. The cluster analysis also revealed treatment-specific and rescue-like protein modules. Overall, our results suggest that adjunctive nebulized Idursulfase ERT enhances the cardiac proteomic changes caused by IV treatment in IDS-KO mice. Proteomics data are available via ProteomeXchange with identifier PXD083242.<\/jats:p>\n                <jats:sec>\n                  <jats:title>Synopsis<\/jats:title>\n                  <jats:p>Adjunctive nebulized Idursulfase ERT enhances the cardiac proteomic changes caused by IV treatment in IDS-KO mice.<\/jats:p>\n                <\/jats:sec>","DOI":"10.64898\/2026.09.07.749889","type":"posted-content","created":{"date-parts":[[2026,9,11]],"date-time":"2026-09-11T14:25:44Z","timestamp":1789136744000},"source":"Crossref","is-referenced-by-count":0,"title":["Adjunctive nebulization of Idursulfase to intravenous treatment enhances cardiac proteome adaptations in IDS-KO mice"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3240-9025","authenticated-orcid":false,"given":"Vinicius M.","family":"Mariani","sequence":"first","affiliation":[{"name":"Department of Orthopaedic Surgery, School of Medicine, Duke University, Durham, NC"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7956-0091","authenticated-orcid":false,"given":"Anat\u00e1lia","family":"Labilloy","sequence":"additional","affiliation":[{"name":"Division of Genetics and Genomics, Boston Children\u2019s Hospital, Boston, MA"},{"name":"Division of Genetics and Genomics, Boston Children\u2019s Hospital, Boston, MA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2329-7623","authenticated-orcid":false,"given":"W. 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