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In this study, we evaluate the biocompatibility and biodistribution of a novel third-generation PEGylated carbosilane dendrimer (G3Si PEG6000) and its siRNA dendriplex with an APOE4-directed siRNA relevant to late-onset Alzheimer\u2019s disease using a tiered, upstream strategy that progresses from BBB-relevant monocultures to a capillary-weighted BBB model and in vivo\/ex vivo biodistribution in mice, in accordance with current recommendations for nanomaterial testing. In endothelial cells, pericytes, and astrocytes, mitochondrial\/redox profiling (MTT, DCF-ROS, and JC-1 \u0394\u03a8m) defined tolerated exposure ranges. Complexation with siRNA consistently attenuated apparent cytotoxicity across cell types, yet both free and complexed formulations elicited modest ROS and dose-dependent \u0394\u03a8m depolarization, indicating persistent mitochondrial stress. In the BBB model, responses were concentration- and formulation-dependent: 10 \u00b5M free dendrimers produced sustained impedance and nuclear confluence loss with sheet-like detachment, whereas the 0.1\u22122.5 \u00b5M free dendrimer and the dendriplex induced transient, recoverable perturbations or increases in impedance and proliferation. In vivo, whole-body IVIS imaging demonstrated prolonged systemic exposure for the dendriplex and an ex vivo kidney-dominant, liver-secondary distribution; no robust dendriplex signal was detected in brain fluorescence by planar NIR-I IVIS under the applied acquisition conditions. Collectively, these data indicate that siRNA complexation broadens the functional window at the BBB model with partially recoverable barrier effects and improved systemic exposure, while not substantially reducing mitochondrial or oxidative stress responses. The results provide a mechanistically informed basis for dose optimization and efficacy testing of this dendrimer\u2212siRNA platform in CNS indications and for advancing this platform in further investigations targeting Alzheimer's disease.<\/jats:p>","DOI":"10.1021\/acsami.6c06027","type":"journal-article","created":{"date-parts":[[2026,7,22]],"date-time":"2026-07-22T13:38:52Z","timestamp":1784727532000},"page":"41387-41403","source":"Crossref","is-referenced-by-count":0,"title":["Multilevel Assessment of a Carbosilane Dendrimer\u2212siRNA Nanoplatform: Cellular Compatibility, Blood\u2212Brain Barrier Model Integrity, and Murine Model Biodistribution"],"prefix":"10.1021","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3093-5945","authenticated-orcid":true,"given":"Serafin","family":"Zawadzki","sequence":"first","affiliation":[{"name":"University of Lodz , , 141\/143 Pomorska St. , ,","place":["Lodz, Poland, 90-236"]},{"name":"University of Lodz , , Matejki 21\/23 , ,","place":["Lodz, Poland, 90-237"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"El\u017cbieta","family":"Ok\u0142a","sequence":"additional","affiliation":[{"name":"University of Lodz , , 141\/143 Pomorska St. , ,","place":["Lodz, Poland, 90-236"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0377-5429","authenticated-orcid":true,"given":"Paula","family":"Ortega L\u00f3pez","sequence":"additional","affiliation":[{"name":"University of Alcal\u00e1 , , ,","place":["Madrid, Spain, 28805"]},{"name":"Networking Research Center on Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN) , ,","place":["Madrid, Spain, 28029"]},{"name":"Ram\u00f3n y Cajal Health Research Institute (IRYCIS) , ,","place":["Madrid, Spain, 28034"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0418-3935","authenticated-orcid":true,"given":"F. Javier","family":"de la Mata","sequence":"additional","affiliation":[{"name":"University of Alcal\u00e1 , , ,","place":["Madrid, Spain, 28805"]},{"name":"Networking Research Center on Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN) , ,","place":["Madrid, Spain, 28029"]},{"name":"Ram\u00f3n y Cajal Health Research Institute (IRYCIS) , ,","place":["Madrid, Spain, 28034"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7227-6864","authenticated-orcid":true,"given":"Maksim","family":"Ionov","sequence":"additional","affiliation":[{"name":"University of Lodz , , 141\/143 Pomorska St. , ,","place":["Lodz, Poland, 90-236"]},{"name":"Mazovian Academy in Plock , , 2 Dabrowskiego Sq. , ,","place":["Plock, Poland, 09-402"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Madara","family":"Krei\u0161mane","sequence":"additional","affiliation":[{"name":"Latvian Biomedical Research and Study Centre , Ratsupites street1 k-1 , ,","place":["Riga, Latvia, LV-1067"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dace","family":"Skrasti\u0146a","sequence":"additional","affiliation":[{"name":"Latvian Biomedical Research and Study Centre , Ratsupites street1 k-1 , ,","place":["Riga, Latvia, LV-1067"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0845-4392","authenticated-orcid":true,"given":"Juris","family":"Jansons","sequence":"additional","affiliation":[{"name":"Latvian Biomedical Research and Study Centre , Ratsupites street1 k-1 , ,","place":["Riga, Latvia, LV-1067"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria","family":"Bryszewska","sequence":"additional","affiliation":[{"name":"University of Lodz , , 141\/143 Pomorska St. , ,","place":["Lodz, Poland, 90-236"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4050-2756","authenticated-orcid":true,"given":"Katarzyna","family":"Mi\u0142owska","sequence":"additional","affiliation":[{"name":"University of Lodz , , 141\/143 Pomorska St. , ,","place":["Lodz, Poland, 90-236"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,7,22]]},"reference":[{"issue":"9","key":"2026081707104866300_cit1","doi-asserted-by":"publisher","first-page":"1598","DOI":"10.1038\/jcbfm.2010.49","article-title":"MRI Estimation of Global Brain Oxygen Consumption Rate","volume":"30","author":"Jain","year":"2010","journal-title":"J. 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