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To understand the influence of chitosan\u2019s molecular weight, dose, payload, and hyaluronic acid coating on in vivo toxicity, immune stimulation, biodistribution and efficacy, precisely characterized chitosans were formulated with unmodified or chemically modified siRNA to control for innate immune stimulation. The hemocompatibility, cytokine induction, hematological and serological responses were assessed. Body weight, clinical signs, in vivo biodistribution and functional target knockdown were monitored. Hemolysis was found to be dose- and MW-dependent with the HA coating abrogating hemolysis. Compared to cationic lipid nanoparticles, uncoated and HA-coated chitosan nanoparticles did not induce immune stimulation or hematologic toxicity. Liver and kidney biomarkers remained unchanged with chitosan formulations, while high doses of cationic lipid nanoparticles led to increased transaminase levels and a decrease in body weight. Uncoated and HA-coated nanoparticles accumulated in kidneys with functional knockdown for uncoated chitosan formulations reaching 60%, suggesting potential applications in the treatment of kidney diseases.<\/jats:p>","DOI":"10.3390\/polym16172547","type":"journal-article","created":{"date-parts":[[2024,9,9]],"date-time":"2024-09-09T09:21:00Z","timestamp":1725873660000},"page":"2547","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Chitosan siRNA Nanoparticles Produce Significant Non-Toxic Functional Gene Silencing in Kidney Cortices"],"prefix":"10.3390","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5672-6930","authenticated-orcid":false,"given":"Mohamad-Gabriel","family":"Alameh","sequence":"first","affiliation":[{"name":"Institute of Biomedical Engineering, Polytechnique Montreal, 2500 Chem. de Polytechnique, Montr\u00e9al, QC H3T 1J4, Canada"},{"name":"Department of Chemical Engineering, Polytechnique Montreal, 2500 Chem. de Polytechnique, Montreal, QC H3T 1J4, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ashkan","family":"Tavakoli Naeini","sequence":"additional","affiliation":[{"name":"Institute of Biomedical Engineering, Polytechnique Montreal, 2500 Chem. de Polytechnique, Montr\u00e9al, QC H3T 1J4, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Garima","family":"Dwivedi","sequence":"additional","affiliation":[{"name":"Institute of Biomedical Engineering, Polytechnique Montreal, 2500 Chem. de Polytechnique, Montr\u00e9al, QC H3T 1J4, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3699-1283","authenticated-orcid":false,"given":"Frederic","family":"Lesage","sequence":"additional","affiliation":[{"name":"Institute of Biomedical Engineering, Polytechnique Montreal, 2500 Chem. de Polytechnique, Montr\u00e9al, QC H3T 1J4, Canada"},{"name":"Department of Chemical Engineering, Polytechnique Montreal, 2500 Chem. de Polytechnique, Montreal, QC H3T 1J4, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7555-8189","authenticated-orcid":false,"given":"Michael D.","family":"Buschmann","sequence":"additional","affiliation":[{"name":"Institute of Biomedical Engineering, Polytechnique Montreal, 2500 Chem. de Polytechnique, Montr\u00e9al, QC H3T 1J4, Canada"},{"name":"Department of Chemical Engineering, Polytechnique Montreal, 2500 Chem. de Polytechnique, Montreal, QC H3T 1J4, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2750-3607","authenticated-orcid":false,"given":"Marc","family":"Lavertu","sequence":"additional","affiliation":[{"name":"Institute of Biomedical Engineering, Polytechnique Montreal, 2500 Chem. de Polytechnique, Montr\u00e9al, QC H3T 1J4, Canada"},{"name":"Department of Chemical Engineering, Polytechnique Montreal, 2500 Chem. de Polytechnique, Montreal, QC H3T 1J4, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,9,9]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1084","DOI":"10.1038\/s41565-019-0591-y","article-title":"The Onpattro story and the clinical translation of nanomedicines containing nucleic acid-based drugs","volume":"14","author":"Akinc","year":"2019","journal-title":"Nat. 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