Arginine–dexamethasone nanoplatform enables biocatalytic remodeling of the cochlear pathological microenvironment

High-intensity noise exposure induces cochlear injury through mechanical trauma, disruption of ionic homeostasis, and secondary oxidative stress, ultimately leading to noise-induced hearing loss (NIHL). Increasing evidence suggests that oxidative stress not only causes direct cellular damage but also drives pathological remodeling of the cochlear microenvironment by triggering persistent inflammatory activation and disrupting endogenous nitric oxide (NO) biocatalytic regulation. However, current therapeutic strategies based solely on antioxidants or anti-inflammatory agents are insufficient to simultaneously restore inflammatory homeostasis and endogenous catalytic regulation within the injured cochlea. Here, we developed a carrier-free arginine–dexamethasone nanoplatform (AD NPs) through a one-step ultrasound-assisted self-assembly strategy to achieve biocatalytic remodeling of the pathological cochlear microenvironment. By integrating the anti-inflammatory activity of dexamethasone with the physiological substrate function of L-arginine for endothelial nitric oxide synthase (eNOS), AD was designed to coordinately suppress inflammatory signaling while supporting endogenous NO biocatalysis. The resulting nanoparticles exhibited an average diameter of approximately 169.9 nm, a positive surface charge (+ 17.18 mV), sustained drug release with accelerated release under H₂O₂-containing conditions, excellent biocompatibility, and prolonged AD-associated fluorescence in the cochlear region following tympanic bulla administration. In H₂O₂-induced cellular models, AD markedly reduced intracellular reactive oxygen species (ROS) accumulation, inhibited NF-κB signaling activation, promoted macrophage polarization toward a pro-repair phenotype, modulated eNOS/iNOS-associated NO biocatalytic regulation, improved endothelial functional phenotypes, and protected HEI-OC1 cells against oxidative injury. Furthermore, L-NAME markedly attenuated the AD-induced recovery of NO-related fluorescence, supporting the involvement of endogenous NOS activity in this response. In a C57BL/6 mouse model of NIHL, prophylactic administration of AD before noise exposure significantly preserved high-frequency hearing, reduced cochlear hair cell loss, maintained ribbon synapse integrity, and corrected the pathological imbalance between eNOS and iNOS within the stria vascularis. At the mechanistic level, AD remodeled the pathological cochlear microenvironment through coordinated suppression of ROS/NF-κB-mediated inflammatory activation and support of endogenous NO biocatalytic regulation, thereby interrupting the reciprocal amplification between inflammatory dysregulation and vascular-associated dysfunction following acoustic injury. Collectively, this work establishes a carrier-free biocatalytic nanoplatform that harnesses endogenous enzymatic regulation to remodel the pathological cochlear microenvironment. This strategy provides a mechanistic framework for microenvironment-oriented biocatalytic nanomedicine and offers a promising protective approach for preventing or mitigating noise-induced cochlear injury. Graphical Design rationale and biocatalytic protective strategy of the Arg–Dex self-assembled nanoplatform for noise-induced hearing loss.