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Although current human pluripotent stem cell (hPSC)\u2010derived otic lineages offer a valuable resource for SGN regeneration, they face challenges in terms of reproducibility and functional maturation. Here, a robust protocol is established to generate human otic neuronal spheroids (hONS) from cryopreserved hPSC\u2010derived pre\u2010placodal ectoderm (PPE) cells. Post\u2010thaw PPE cells retained high purity and differentiation efficiency comparable to fresh PPE cells. These self\u2010assembled hONS differentiated into functionally mature SGN\u2010like neurons, showing specific maker expression, electrophysiological activity, AMPA receptor\u2010mediated glutamate response, and extensive neurite extension. In tripartite cocultures incorporating murine cochlear explants and human cortical organoids, hONS formed bidirectional functional synaptic connections, validated through live\u2010cell imaging, optogenetic stimulation, and synaptic immunostaining. Notably, hONS exhibited heightened sensitivity to ototoxic insults. Short\u2010term cisplatin exposure induced dose\u2010dependent alterations in cellular and calcium dynamics, whereas prolonged exposure impaired glutamatergic neural functionality and triggered progressive neuronal death. Co\u2010treatment with sodium thiosulfate attenuated cisplatin\u2010induced damage. The hONS model also demonstrated concentration\u2010dependent toxicity to neomycin. Collectively, this hONS model provides a reliable platform for investigating SGN regeneration and conducting preclinical evaluation of ototoxic drug.<\/jats:p>","DOI":"10.1002\/advs.202505663","type":"journal-article","created":{"date-parts":[[2025,11,21]],"date-time":"2025-11-21T10:04:06Z","timestamp":1763719446000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Cryopreserved Human Otic Neuronal Spheroids Self\u2010assemble for Functional Connectivity Analysis and Long\u2010term Ototoxicity Evaluation"],"prefix":"10.1002","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5237-0458","authenticated-orcid":false,"given":"Gaoying","family":"Sun","sequence":"first","affiliation":[{"name":"Department of Otolaryngology\u2010Head and Neck Surgery Shandong Provincial ENT Hospital Shandong University  Jinan 250022 China"},{"name":"Shandong Institute of Otorhinolaryngology  Jinan 250022 China"},{"name":"Key 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