Ti(3)C(2)T(x)MXene Composite 3D Hydrogel Potentiates mTOR Signaling to Promote the Generation of Functional Hair Cells in Cochlea Organoids

Organoids have certain cellular composition and physiological features in common with real organs, making them promising models of organ formation, function, and diseases. However, Matrigel, the commonly used animal-derived matrices in which they are developed, has limitations in mechanical adjustability and providing complex physicochemical signals. Here, the incorporation of Ti(3)C(2)T(x)MXene nanomaterial into Matrigel regulates the properties of Matrigel and exhibits satisfactory biocompatibility. The Ti(3)C(2)T(x)MXene Matrigel composites (MXene-Matrigel) regulate the development of Cochlear Organoids (Cochlea-Orgs), particularly in promoting the formation and maturation of organoid hair cells. Additionally, regenerated hair cells in MXene-Matrigel are functional and exhibit better electrophysiological properties compared to hair cells in Matrigel. MXene-Matrigel potentiates the amycin (mTOR) signaling pathway to promote hair cell differentiation, and mTOR signaling inhibition restrains hair cell differentiation. Moreover, MXene-Matrigel facilitates innervation establishment between regenerated hair cells and spiral ganglion neurons (SGNs) growing from the Cochlea modiolus in a co-culture system, as well as promotes synapse formation efficiency. The approach overcomes some limitations of the Matrigel-dependent culture system and greatly accelerates the application of nanomaterials in organoid development and research on therapies for hearing loss.