Ferritin-based targeted delivery of cimifugin to hair cells provides strong protection against hearing loss

Abstract

Deafness and hearing loss are the most widely distributed sensory organ disabilities worldwide, and their negative impact places them at the top of the global burden of diseases list. Therefore, the need to develop new and efficient prevention and treatment strategies is urgent. Here, we successfully developed a noninvasive drug delivery system involving a ferritin (Fn)-based drug delivery platform. To further increase therapeutic efficacy, we loaded cimifugin (Ci), an active ingredient extracted from Cimicifuga racemosa, into Fn to form the complex Ci@Fn. Ci@Fn was injected through the retroauricular round window membrane and then transported to the basement membrane along with the flow of ectolymphatic and endolymphatic fluids. Further through the targeting function of Fn, Ci@Fn was able to precisely target hair cells (HCs). Subsequently, Ci@Fn is endocytosed by HCs and releases Ci in lysosomes, exerting its protective effect on HCs. Neonatal mouse model experiments revealed that Ci@Fn significantly reduced cisplatin (Cis)-induced cochlear hair cell damage and prevented hair cell loss and apoptosis. In addition, RNA sequencing analysis revealed that Ci@Fn attenuates Cis-induced ototoxicity mainly by modulating the PI3K-Akt signaling pathway. Finally, in validation experiments in an adult mouse model of noise-induced hearing damage, we found that Ci@Fn had a significant hearing-protective effect, superior to the current gold standard treatment (dexamethasone). These findings demonstrate that Ci@Fn is an innovative and efficient solution for hearing loss treatment and lays a solid foundation for future clinical applications.