A coacervate-based redox-responsive cytoplasmic delivery system for antioxidant macromolecule to rescue sensorineural hearing loss

Sensorineural hearing loss (SNHL) is a prevalent global health issue, primarily caused by excessive generation of reactive oxygen species (ROS) due to acoustic trauma, aging, and ototoxic drugs. Natural antioxidant enzymes, such as catalase (CAT), possess remarkable ROS scavenging capabilities and hold significant potential for SNHL treatment. However, their clinical application is hindered by inefficient delivery and limited stability. Here, we introduce a novel peptide-oligosaccharide conjugate, sELP-ON, which forms coacervate microdroplets via liquid–liquid phase separation. These microdroplets efficiently encapsulate and stably carry CAT, releasing it in a glutathione-triggered, redox-responsive manner. The CAT-loaded sELP-ON (sELP-ON@CAT) enhanced cellular uptake through direct cytoplasmic internalization and demonstrates a more robust ROS scavenging activity than naked CAT treatment. Local administration of sELP-ON@CAT in an acoustic injury mouse model effectively rescues hearing loss by reducing cochlear ROS levels, thereby mitigating hair cell loss, ribbon synapse depletion, stria vascularis shrinkage and spiral ganglion neuron degeneration. In summary, our innovative coacervate microdroplet system enables targeted, redox-responsive cytoplasmic delivery of macromolecular antioxidants, offering a novel and effective strategy for treating SNHL.