Intratympanic injection of human umbilical cord mesenchymal stem cell derived small extracellular vesicles for refractory sudden sensorineural hearing loss: a Phase 1 trial

BACKGROUND: Refractory sudden sensorineural hearing loss (RSSNHL) remains a therapeutic challenge with limited effective treatment options. Human umbilical cord mesenchymal stem cell-derived small extracellular vesicles (hucMSC-sEVs) have demonstrated otoprotective and regenerative potential in preclinical studies. This Phase 1 trial evaluated the safety of intratympanic hucMSC-sEVs in patients with RSSNHL. METHODS: This single-center, open-label, single-arm clinical study enrolled RSSNHL patients between June and September 2025 (ChiCTR2500103765). Participants received intratympanic hucMSC-sEVs for five consecutive days across four dose cohorts, ranging from 8 × 10⁸ to 1 × 10¹¹ particles/mL. Follow-up assessments were conducted at 1, 2, 4, and 8 weeks after treatment, during which adverse events (AEs) were recorded, and hearing outcomes were evaluated. RESULTS: Twelve of the thirteen enrolled patients completed the 8-week follow-up. Intratympanic administration of hucMSC-sEVs was well tolerated across all dose levels, with no dose-limited toxicity or serious AEs. The most common AEs were ear pain (5/12), ear fullness (3/12), and transient dizziness (2/12), all characteristic of intratympanic injection and resolving without intervention. CONCLUSIONS: In this Phase 1 study, intratympanic hucMSC-sEVs were well tolerated and showed preliminary signals of hearing improvement. Responses were observed only in patients receiving lower dose levels (8 × 10⁸ and 4 × 10⁹ particles/mL) and in those treated within a shorter disease window (≤ 22 days). These exploratory findings require confirmation in larger controlled trials. Trial Registration This study was registered on June 5,2025, at Chinese Clinical Trial Registry (ChiCTR2500103765).