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Local drug delivery via the middle ear represents the most effective approach for treating inner ear disease. However, therapeutic efficacy is constrained by poor middle ear retention and limited permeability across the round window membrane (RWM). Quercetin (QU) exhibits potent activity against CDDP-induced cytotoxicity but suffers from delivery challenges. To address this, we developed amino-functionalized mesoporous silica nanoparticles (NH2-MSNs) loaded with QU (QU-N-MSNs), leveraging the permselective properties of the RWM. This system was noninvasively administered to the cochlea via trans-tympanic delivery. The synthesized QU-N-MSNs demonstrated a uniform particle size of approximately 116\u2013124 nm, positive charge, and sustained drug release properties. Compared to free QU, QU-N-MSNs demonstrated significantly enhanced antiapoptotic and cytoprotective activities in vitro. In vivo studies confirmed nanoparticle retention within the inner ear for \u226514 days post administration and efficient RWM penetration. Pretreatment with QU-N-MSNs prior to CDDP exposure in murine models substantially mitigated ototoxicity, as evidenced by reduced hearing threshold shifts across multiple frequencies, preservation of hair cells (HCs) and spiral ganglion neurons (SGNs), and attenuation of mitochondrial-mediated SGN apoptosis. These findings establish QU-N-MSNs as an effective RWM-penetrating delivery platform, offering a promising strategy to enhance hydrophobic drug bioavailability in the inner ear and prevent CDDP-induced ototoxicity.<\/jats:p>","DOI":"10.1021\/acsabm.5c01746","type":"journal-article","created":{"date-parts":[[2025,11,3]],"date-time":"2025-11-03T19:22:39Z","timestamp":1762197759000},"page":"10419-10435","source":"Crossref","is-referenced-by-count":8,"title":["Mesoporous Silica\nNanoparticles for Quercetin-Controlled\nDelivery to Protect Cisplatin-Induced Ototoxicity"],"prefix":"10.1021","volume":"8","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8712-7511","authenticated-orcid":true,"given":"Muyao","family":"Shen","sequence":"first","affiliation":[{"name":"Nanjing Drum Tower Hospital, Clinical College of Nanjing University of Chinese Medicine , , ,","place":["Nanjing, China, 210046"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Handong","family":"Wang","sequence":"additional","affiliation":[{"name":"Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University , , ,","place":["Nanjing, China, 210008"]},{"name":"Research Institute of Otolaryngology , ,","place":["Nanjing, China, 210061"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junfeng","family":"Liu","sequence":"additional","affiliation":[{"name":"Dalian University of Technology , , ,","place":["Dalian, China, 116024"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zixin","family":"Zhou","sequence":"additional","affiliation":[{"name":"Gulou Clinical Medical College, Jiangsu University , , ,","place":["Zhenjiang, China, 212000"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xingguang","family":"Wu","sequence":"additional","affiliation":[{"name":"Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University , , ,","place":["Nanjing, China, 210008"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hanqi","family":"Fan","sequence":"additional","affiliation":[{"name":"Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University , , ,","place":["Nanjing, China, 210008"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haoliang","family":"Du","sequence":"additional","affiliation":[{"name":"Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University , , ,","place":["Nanjing, China, 210008"]},{"name":"Research Institute of Otolaryngology , ,","place":["Nanjing, China, 210061"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yue","family":"Qiu","sequence":"additional","affiliation":[{"name":"Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University , , ,","place":["Nanjing, China, 210008"]},{"name":"Research Institute of Otolaryngology , ,","place":["Nanjing, China, 210061"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dingding","family":"Liu","sequence":"additional","affiliation":[{"name":"Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University , , ,","place":["Nanjing, China, 210008"]},{"name":"Research Institute of Otolaryngology , ,","place":["Nanjing, China, 210061"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dengbin","family":"Ma","sequence":"additional","affiliation":[{"name":"Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University , , ,","place":["Nanjing, China, 210008"]},{"name":"Research Institute of Otolaryngology , ,","place":["Nanjing, China, 210061"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yong","family":"Wang","sequence":"additional","affiliation":[{"name":"Jiangsu Provincial Hospital of Integrated Traditional Chinese and Western Medicine , , ,","place":["Nanjing, China, 210028"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhao","family":"Tang","sequence":"additional","affiliation":[{"name":"Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University , , ,","place":["Nanjing, China, 210008"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shu","family":"Yang","sequence":"additional","affiliation":[{"name":"The First Clinical Medical College of Nanjing University of Chinese Medicine , ,","place":["Nanjing, China, 210029"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuan","family":"Zhang","sequence":"additional","affiliation":[{"name":"Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University , , ,","place":["Nanjing, China, 210008"]},{"name":"Research Institute of Otolaryngology , ,","place":["Nanjing, China, 210061"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tianhong","family":"Zhang","sequence":"additional","affiliation":[{"name":"First Affiliated Hospital of Harbin Medical University , , , ,","place":["Harbin, Heilongjiang, China, 150001"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4539-5929","authenticated-orcid":true,"given":"Xia","family":"Gao","sequence":"additional","affiliation":[{"name":"Nanjing Drum Tower Hospital, Clinical College of Nanjing University of Chinese Medicine , , ,","place":["Nanjing, China, 210046"]},{"name":"Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University , , ,","place":["Nanjing, China, 210008"]},{"name":"Research Institute of Otolaryngology , ,","place":["Nanjing, China, 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Biochem."},{"issue":"2","key":"2026073107101356800_cit12","doi-asserted-by":"publisher","DOI":"10.1016\/j.imbio.2022.152324","article-title":"Quercetin acts as a novel anti-cancer drug to suppress\ncancer aggressiveness\nand cisplatin-resistance in nasopharyngeal carcinoma (NPC) through\nregulating the yes-associated protein\/Hippo signaling pathway","volume":"228","author":"Li","year":"2023","journal-title":"Immunobiology"},{"issue":"5","key":"2026073107101356800_cit13","doi-asserted-by":"publisher","first-page":"1133","DOI":"10.1111\/bph.15350","article-title":"Quercetin induces p53-independent\ncancer cell death through lysosome activation by the transcription\nfactor EB and Reactive Oxygen Species-dependent ferroptosis","volume":"178","author":"Wang","year":"2021","journal-title":"Br. J. Pharmacol."},{"key":"2026073107101356800_cit14","doi-asserted-by":"publisher","DOI":"10.1155\/2020\/9242601","article-title":"Quercetin Suppresses\nAOM\/DSS-Induced Colon Carcinogenesis through Its Anti-Inflammation\nEffects in Mice","volume":"2020","author":"Lin","year":"2020","journal-title":"J. Immunol. Res."},{"key":"2026073107101356800_cit15","doi-asserted-by":"publisher","DOI":"10.1016\/j.biopha.2024.116985","article-title":"Quercetin\ninhibits chronic stress-mediated progression of triple-negative breast\ncancer by blocking \u03b2(2)-AR\/ERK1\/2 pathway","volume":"177","author":"Zhang","year":"2024","journal-title":"Biomed. Pharmacother."},{"key":"2026073107101356800_cit16","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejmech.2021.114068","article-title":"Quercetin\nderivatives: Drug design, development, and\nbiological activities, a review","volume":"229","author":"Alizadeh","year":"2022","journal-title":"Eur. J. Med.\nChem."},{"issue":"11","key":"2026073107101356800_cit17","doi-asserted-by":"publisher","first-page":"1631","DOI":"10.3390\/ph16111631","article-title":"Quercetin\nas a Therapeutic\nProduct: Evaluation of Its Pharmacological Action and Clinical Applications-A\nReview","volume":"16","author":"Mirza","year":"2023","journal-title":"Pharmaceuticals"},{"issue":"1","key":"2026073107101356800_cit18","doi-asserted-by":"publisher","DOI":"10.3390\/molecules21010108","article-title":"Application of Bioactive\nQuercetin\nin Oncotherapy: From Nutrition to Nanomedicine","volume":"21","author":"Nam","year":"2016","journal-title":"Molecules"},{"issue":"3","key":"2026073107101356800_cit19","doi-asserted-by":"publisher","first-page":"290","DOI":"10.1016\/j.nantod.2013.04.007","article-title":"Nonporous silica nanoparticles\nfor nanomedicine application","volume":"8","author":"Tang","year":"2013","journal-title":"Nano Today"},{"key":"2026073107101356800_cit20","doi-asserted-by":"publisher","DOI":"10.1016\/j.addr.2023.115049","article-title":"Biosafety\nof mesoporous silica nanoparticles; towards clinical translation","volume":"201","author":"Le\u0301rida-Viso","year":"2023","journal-title":"Adv. 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Nanobiotechnol."},{"key":"2026073107101356800_cit36","doi-asserted-by":"publisher","first-page":"2","DOI":"10.1016\/j.addr.2016.01.004","article-title":"Advances in\nnano-based\ninner ear delivery systems for the treatment of sensorineural hearing\nloss","volume":"108","author":"Li","year":"2017","journal-title":"Advanced drug delivery reviews"},{"issue":"4","key":"2026073107101356800_cit37","doi-asserted-by":"publisher","first-page":"250","DOI":"10.3390\/pharmaceutics10040250","article-title":"Dealing with\nSkin and Blood-Brain Barriers: The Unconventional Challenges of Mesoporous\nSilica Nanoparticles","volume":"10","author":"Nigro","year":"2018","journal-title":"Pharmaceutics"},{"key":"2026073107101356800_cit38","doi-asserted-by":"publisher","DOI":"10.1016\/j.foodchem.2024.138561","article-title":"Determination of free\nfatty acids in edible oil based on hollow mesoporous silica nanoparticles","volume":"443","author":"Wang","year":"2024","journal-title":"Food Chem."},{"issue":"3","key":"2026073107101356800_cit39","doi-asserted-by":"publisher","first-page":"229","DOI":"10.3109\/07388551.2012.685860","article-title":"Mesoporous silica nanoparticles\nin nanotechnology","volume":"33","author":"Douroumis","year":"2013","journal-title":"Critical Reviews in Biotechnology"},{"issue":"2","key":"2026073107101356800_cit40","doi-asserted-by":"publisher","DOI":"10.1002\/wnan.1767","article-title":"Direct\nnose to the brain nanomedicine delivery presents a formidable challenge","volume":"14","author":"Yokel","year":"2022","journal-title":"Wiley Interdiscip. 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