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Ototoxicity represents a major adverse side-effect of cis-diamminedichloroplatinum-II (cisplatin, CDDP). The mitogen-activated protein kinase (MAPK) pathway is thought to play a central role in potentiating the apoptotic effect of CDDP within the cochlea. We hypothesized that prophylactic inhibition of MAPK signaling, using small interfering RNA (siRNA), might confer a protective effect against CDDP-induced apoptosis within the auditory sensory epithelia. To enhance the therapeutic utility of this approach, we synthesized biocompatible siMAPK1-loaded nanoparticles (NPs) and performed physicochemical characterizations for size, morphology, drug loading and release kinetics, using dynamic light scattering, electron microscopy and spectrophotometric analyses, respectively. Our findings show 183.88 ± 6.26 nm-sized spherical siMAPK1-loaded NPs with −27.12 ± 6.65 mV zeta potential and 112.78 ± 0.24 pmol/mg of siMAPK1 loading that exhibit a sustained release profile for prolonged therapeutic efficacy. Synthesized NPs were validated for biocompatibility and prophylactically protected against CDDP-induced cytotoxicity in HEI-OC1 cells and hair cell loss in murine organotypic cochlear explants. Our study confirms a pivotal role for MAPK1 signaling as a potentiating factor for CDDP-induced apoptosis and cochlear hair cell loss, and highlights siMAPK1 NP treatment as a therapeutic strategy for limiting the ototoxic side-effects associated with systemic CDDP administration.