Dopamine-modified Ti₃C₂T_x MXene promotes supporting cell pluripotency and hair cell regeneration in cochlear organoid culture

Sensorineural hearing loss (SNHL), predominantly resulting from the irreversible loss of cochlear hair cells, remains a clinical challenge without effective treatments. Recently, neuromodulation strategies based on two-dimensional nanomaterials have shown regenerative potential, with MXene standing out due to its excellent electrical conductivity, biocompatibility, and modifiable surface properties. Hair cells (HCs) and supporting cells (SCs) originate from the same prosensory cells, with previous work showing that MXene (especially Ti₃C₂T_x) incorporation in Matrigel can promote HCs formation with SCs in cochlear organoid culture. However, the MXene is prone to oxidation, losing the conductivity and catalytic activity of this material in Matrigel during HC regeneration. In this study, we modified MXene with dopamine (DA-MXene) that mimics neurotransmitter functions to promote HC regeneration. We found that DA-MXene significantly enhanced the proliferation and survival of SCs in organoid culture. HC formation was also upregulated in DA-MXene treated cochlear explant culture compared with MXene samples. Mechanistic studies indicated that DA-MXene further activated signaling pathways that regulate pluripotency of stem cells compared with MXene, which is vital for restoring the plasticity of SCs. Collectively, this work proposes an innovative nanomaterial-based approach that combines chemical modification and electroactive stimulation, offering a promising strategy for regenerating HCs in SNHL.