Mitochondria-homing peptide functionalized nanoparticles performing dual extracellular/intracellular roles to inhibit aminoglycosides induced ototoxicity.

One of the major challenges in the treatment of hearing loss is the low efficacy of therapeutic candidates. To achieve the optimum drug efficacy, we designed a novel peptide (D-Arg-Dmt-Arg-Phe-NH)-mediated mitochondrial targeted delivery nanosystem for a promising candidate, geranylgeranylacetone (GGA). The zebrafish lateral line system, a robust model for mammalian hair cells, was used to identify the efficacy against gentamicin, a well-known ototoxic agent. The nanosystem facilitated lysosomal escape and mitochondrial accumulation, and thus conferred superior protective efficacy against a wide range of gentamicin compared with unmodified NPs and free drugs. Meanwhile, peptides-modified NPs internalized hair cells via both of dynamin-dependent and independent routes, following a classic endocytic or autophagy pathway. Although extracellular action via MET channels, the primary protective mechanism underlying peptides-modified NPs was revealed due to their intracellular interaction. Thus, our nanoplatform provided a general strategy to enhance the clinical efficacy of a broad range of drugs in the treatment of hearing loss.