Auditory Research publications

The brain computes sound location from auditory spatial cues. Humans and barn owls both localize sounds accurately, yet they rely on fundamentally different cue configurations shaped by their ear anatomy and neural circuitry. In humans, symmetrical ears provide interaural time and level differences (ITD and ILD) for horizontal localization, while vertical localization depends primarily on high‐frequency, monaural spectral cues generated by the pinnae. Barn owls, by contrast, possess asymmetrical ears and use binaural cues for both azimuth and elevation. Because auditory pathways are tuned to species‐specific cue statistics, it remains unclear whether humans can adapt when binaural level cues are also made informative about elevation. We tested this by fitting human listeners with asymmetric ear molds that disrupted normal spectral cues, introduced elevation‐dependent ILDs, and left ITDs unaffected. Participants wore the molds during daily life and were tested with broadband, high‐pass, and low‐pass noise bursts. Acute mold exposure severely degraded elevation localization, whereas horizontal localization remained largely unaffected. With prolonged exposure, elevation localization improved, but adaptation was limited, variable across listeners, and fluctuated across sessions. Improvement was strongest for broadband sounds. Because broadband and high‐pass sounds both contained high‐frequency information, this broadband advantage cannot be explained by access to additional spectral cues alone. Instead, it suggests that low‐frequency ITDs helped listeners exploit the altered binaural cue structure, including the elevation‐dependent ILDs introduced by the molds. These findings show that humans can partially adapt to asymmetric outer‐ear acoustics when complementary spatial cues help resolve ambiguity in the altered cue structure.

This study examined whether interaural amplitude modulation (AM) coherence influences binaural pitch fusion in cochlear implant (CI) users. Fourteen adults, including seven bimodal and seven bilateral CI users, completed fusion-range measurements using dichotic stimuli under unmodulated, coherent AM and two incoherent AM conditions involving interaural AM-phase and AM-rate mismatches. Coherent AM consistently broadened fusion ranges, often doubling those in the unmodulated condition, even with shallow modulation depth. In contrast, incoherent AM, including interaural phase or rate mismatches, narrowed fusion. These findings indicate that temporal-envelope coherence facilitates binaural integration in CI users, emphasizing its importance for auditory processing and CI sound-processing design.

Background Hearing loss primarily results from irreversible cochlear hair cell (HC) damage caused by factors such as noise, aging, genetics, and ototoxic drugs including cisplatin. Currently, there are no effective clinical otoprotective agents available. The natural compound paeonol, derived from Paeonia suffruticosa, exhibits potential anti‐inflammatory and antioxidant properties, positioning it as a promising therapeutic candidate given the central roles of oxidative stress and inflammation in hearing loss pathogenesis. Methods and Results Using mouse cochlear explant cultures, we demonstrated that paeonol protects against cisplatin‐induced HC damage in a concentration‐dependent manner and reduces the accumulation of MitoSOX, TNF‐α, and IL‐6. In vivo, paeonol administration not only prevented cisplatin‐induced HC loss and inner HC synaptic degeneration but also conferred protection against noise‐induced HC damage and hearing loss, demonstrating broad otoprotective efficacy. Mechanistically, RNA‐seq analysis revealed that paeonol exerts its protective effect partly by preventing ribosome biogenesis dysfunction, thereby ensuring normal protein synthesis in HCs. Conclusions Together, our work demonstrates the efficacy of paeonol across multiple models and reveals a potential protective mechanism, paving the way for its development as a much‐needed otoprotective drug.

The transcription factor ATOH1 is a master regulator of mechanosensory hair-cell (HC) development in the ear. Here, we report that its target gene Casz1 regulates the maturation of outer HCs (OHCs). Genetic deletion of Casz1 during (but not after) cochlear development in the mouse caused: hearing loss; disorganization of mechanosensory stereocilia bundles in OHCs; reduced F-actin density in OHC cuticular plates; progressive OHC loss; and mild morphological alterations in inner HCs. This deletion also altered gene expression, delaying downregulation of genes expressed in immature OHCs, including the actin regulator-encoding gene Coro2a, and accelerating upregulation of genes expressed in mature OHCs. Deleting Coro2a in Casz1 mutant mice restored F-actin density in cuticular plates but increased stereocilia bundle disorganization and hearing thresholds, revealing that CORO2A provides an overall beneficial effect. Our data indicate that CASZ1 regulates transcriptional and morphological maturation of OHCs, and that CASZ1 in maturing HCs is necessary for hearing.

The inferior colliculus (IC) is a critical auditory processing center. IC neurons exhibit diverse responses to different sound features, but how IC neurons encode co-varying sound features—such as both the direction and intensity of a frequency-modulated (FM) sweep—is poorly understood. Here, we show that individual IC neurons and neuronal populations multiplex information about FM sweep direction, frequency range, and speed through distinct coding strategies, including both spike timing patterns and overall firing rate.

Pathogenic variants in the calcium and integrin-binding protein 2 (CIB2) are among the leading causes of nonsyndromic prelingual hearing loss (DFNB48). Loss of Cib2 in mice causes severe stereocilia bundle defects, impaired mechanoelectrical transduction (MET), and profound hearing loss. To determine whether a critical window of opportunity exists to restore the stereocilia architecture and to rescue hearing function, we developed and investigated the effect of adeno-associated virus (AAV)-mediated gene delivery in Cib2 mutant mice. A single administration of the AAV-Cib2 vector was performed via semicircular canal injections in Cib2ko/ko mice at several different ages within the early postnatal period. We observed sustained, but partial, recovery of hearing function and restoration of stereocilia architecture in the apical to middle cochlear turns in mice having received AAV-Cib2 between postnatal day 0 (P0) and P4. Both CIB2 and a closely related protein family member, CIB3, are known to bind to TMC1/2 proteins and regulate MET function. Thus, we also investigated the impact of human CIB3 (hCIB3) overexpression on hearing in Cib2ko/ko mice. Intriguingly, administration of AAV-CIB3 gene via semicircular canal injections at P0-P1 also restored hearing function at frequencies corresponding to the apical to middle cochlear turns in Cib2ko/ko mice. Taken together, our data provide a critical timeline in which stereocilia architecture and hearing function can be restored in CIB2-deficient mice and lay the foundation for future gene therapy trials for DFNB48 patients.

Aging and noise over-exposure lead to complex mixtures of cochlear degradation that impair the structure and function of outer hair cells (OHCs), inner hair cells (IHCs), and the cochlear nerve. However, IHC damage and cochlear synaptopathy (CS) remain pathologies "hidden" from the audiogram. This study aimed to compare and contrast the physiological signatures of these two popular and distinct exposure paradigms using promising non-invasive assays: Envelope Following Responses (EFRs), Auditory Brainstem Response (ABRs), Wideband Middle-Ear Muscle Reflexes (WB-MEMRs), and Distortion Product Otoacoustic Emissions (DPOAEs). We utilized chinchilla models of carboplatin exposure (CA) (N = 4) and temporary threshold shift (TTS) noise-induced CS (N = 4) to compare the physiological signatures of each type of exposure. While both groups showed unchanged ABR thresholds two weeks after exposure, EFRs, ABR Wave 5/1 ratios, and MEMRs showed distinct effects of exposure. CA and TTS exposures showed differences in the pattern and degree of decreased EFR "peakiness" across different stimulus modulation types (e.g., sinusoidal vs. rectangular). Significant elevations in ABR Wave 5/1 ratios were less-pronounced in the TTS-exposed animals. Reduced WB-MEMR amplitudes and increased WB-MEMR thresholds occurred in both groups, although this effect was more pronounced for TTS. Opposite trends in DPOAE amplitudes suggest that effects on OHC integrity and auditory efferent physiology may differ between the two exposure types and their induced pathologies. Overall, these results suggest a combination of EFR "peakiness", ABR Wave 5/1 ratio, and WB-MEMR may be useful for profiling IHC dysfunction and CS as potentially distinct forms of hidden hearing loss.

Fragile X syndrome (FXS) is a neurodevelopmental disorder caused by CGG trinucleotide repeat expansion in the fragile X messenger ribonucleoprotein 1 (FMR1) gene and the resulting loss of fragile X messenger ribonucleoprotein (FMRP). Gene therapy using recombinant adeno-associated virus (AAV) to restore FMRP expression, particularly in the brain, is a promising therapeutic strategy targeting the underlying cause of FXS. We examined the impact of AAV serotype 9 (AAV9)-mediated expression of a brain-abundant human FMRP isoform (isoform 7) driven by a fragment of the human FMR1 promoter on circuit and behavioral dysfunctions in the male Fmr1 knockout (KO) mouse, FXS model. Following intracerebroventricular (i.c.v.) injection of AAV9-NG276 into neonatal KO mice at a low (1e11 vg/animal) or high (3e11 vg/animal) dose, we assessed cortical phenotypes using electroencephalography (EEG) recordings and behavioral testing. High-dose AAV9-NG276 normalized baseline gamma power, improved sound-evoked responses, and reduced background neural activity. Analysis of behavioral deficits in adult KO mice showed that high-dose neonatal AAV9-NG276 delivery normalized exploratory behaviors, social preference, and probabilistic reversal learning. Thus, early AAV-mediated delivery of human FMR1 isoform 7 ameliorates cortical dysfunction and behavioral deficits in a murine FXS model and suggests that widespread cortical biodistribution is required for therapeutic benefit.

Objectives. Spatial mapping of sound frequencies along the auditory pathway is refined through sound-evoked activity during early development. However, how neonatal auditory deprivation alters this organization remains unclear. This study examined frequency-specific spatial representations in the inferior colliculus (IC) using targeted low-frequency (apical) and high-frequency (basal) cochlear stimulation, enabling direct evaluation of low-frequency pathway integrity after neonatal deafness.Methods. Sixteen Sprague-Dawley rats (8 normal-hearing [NH] and 8 neonatally deafened [ND]) were studied. Neonatal deafness was induced by daily kanamycin injections from postnatal days 4 to 17. At 8–10 weeks of age, all animals underwent unilateral cochlear implantation with bipolar electrode pairs positioned in apical and basal cochlear regions to activate low- and high-frequency pathways. Multiunit responses were recorded from the contralateral IC using a multichannel linear electrode array. Spatial tuning curves (STCs) based on cumulative discriminability were used to assess thresholds, spread of excitation, and tonotopic precision. Spiral ganglion neuron (SGN) density was quantified histologically.Results. Despite 48%–67% SGN loss across cochlear turns, electrically evoked auditory brainstem response thresholds and IC thresholds were comparable between groups, indicating preserved peripheral excitability. However, ND rats exhibited significantly broader STCs (P=0.002) and reduced dorsoventral separation of apical and basal best sites (1.18± 0.67 mm vs. 1.80±0.40 mm, P=0.039), reflecting degraded central tonotopic precision. The effects were most pronounced for apical (low-frequency) stimulation, consistent with the selective vulnerability of low-frequency pathways to early auditory deprivation.Conclusion. These findings provide direct physiological evidence that early auditory experience is critical for refining frequency-organized connectivity in the auditory midbrain. The preferential degradation of apical (low-frequency) spatial tuning offers translational insights for optimizing stimulation strategies in early-onset deafness.

Background Approximately one in three adults aged 65–74 years reports hearing difficulty, including age-related hearing loss (AHL, presbycusis). The C57BL/6 mouse is widely used in preclinical AHL research because it develops AHL relatively early. Calorie restriction (CR) attenuates AHL and improves healthspan and longevity in this strain. A recently developed transgenic C57BL/6 mouse expressing naked mole-rat hyaluronan synthase 2 ( nmrHas2 ), which produces very high molecular mass hyaluronan (vHMM-HA), also exhibits improved healthspan, reduced inflammaging, and increased longevity. Therefore, we evaluated nmrHas2 mice for evidence of alleviated AHL. Objective To determine whether AHL is attenuated in nmrHas2 mice . Methods This study supplemented a larger investigation of nmrHas2 and female reproductive aging. Tamoxifen administered at 1 month induced ubiquitous nmrHas2 expression in nmrHas2+ females; nmrHas2− controls received tamoxifen or vehicle. Auditory brainstem response (ABR) testing was performed approximately 2 weeks before mice reached 3 or 12 months of age. Cochleae and reproductive tissues were collected following euthanasia approximately 2 weeks later. Results ABR thresholds to clicks and six tones (4–32 kHz) showed marked hearing loss from 3 to 12 months of age in both nmrHas2+ mice and controls, with no evidence that nmrHas2 attenuated AHL. Cochlear nmrHas2 expression in nmrHas2+ mice was confirmed by quantitative RT-PCR. Conclusion Ubiquitous nmrHas2 expression did not attenuate AHL in C57BL/6 mice despite previously reported benefits for other aging phenotypes. These findings contrast with CR, suggesting that vHMM-HA and CR influence aging through distinct mechanisms.

The ability to detect deviations from expected sensory input is fundamental for adaptive behavior. We recorded electrocorticographic activity from the auditory (AC) and prefrontal (PFC) cortices of behaving macaques during an auditory oddball task to probe the cortical dynamics of predictive processing. Repetition of standard stimuli evoked suppression and facilitation in AC and strong low-frequency (2 Hz) enhancement in PFC, accompanied by bidirectional delta-band GC-defined interactions indicative of a shared predictive state. Deviant stimuli triggered earlier AC responses followed by PFC activation and increased GC-defined directed interactions across theta, alpha, and conventional gamma bands. Behavioral engagement amplified both repetition-related and deviance-related ECoG responses, strengthening cortical network coordination. Together, these findings reveal behaviorally gated auditory–prefrontal dynamics that are consistent with hierarchical predictive-processing accounts, while also allowing for contributions from repetition-, novelty-, and salience-related mechanisms.

Noise-induced hearing loss (NIHL) is a major public health problem caused by damage to cochlear hair cells, synapses, and spiral ganglion neurons (SGNs). Since effective treatments are lacking, we investigated cellular stress responses induced by moderate and loud noise in a mouse model of cochlear synaptopathy. RNA sequencing and spatial transcriptomics revealed that noise exposure elicited a robust but transient upregulation of endoplasmic reticulum chaperones and proteasome subunits in SGNs and their supporting cells. To target this response, we administered TRC051384, a small-molecule activator of the heat shock transcription factor Hsf1, prior to noise exposure. TRC051384 crossed the blood–labyrinth barrier and reached the cochlea, induced heat shock protein gene expression, and restored ubiquitin–proteasome function in SGNs. Notably, TRC051384 treatment enhanced auditory brainstem response threshold recovery, preserved Wave I amplitudes, and maintained ribbon synapse density. Together with the existing literature, these findings identify proteotoxic stress in spiral ganglion neurons as a contributor to noise-induced hearing loss and support pharmacological activation of HSF1 as a promising therapeutic strategy.

Difficulties understanding speech in noise remain a common complaint even among listeners with normal hearing sensitivity, highlighting the need for objective, more effective measures of real-world listening. The goal of this study was to validate the use of a novel, chirped-speech (Cheech) stimulus—continuous, naturally-spoken speech fused with chirps designed to elicit robust auditory evoked potentials—to characterize relationships between speech recognition, listening effort, and auditory neural encoding. Twenty-five normal-hearing adults completed a sentence-recognition task using both original (unmodified) and Cheech-modified AzBio sentence lists in quiet, +3 dB, and −3 dB signal-to-noise ratio (SNR) conditions while neural responses from the brainstem through cortex were recorded simultaneously. Speech recognition remained near ceiling in quiet but declined with decreasing SNR for both original and Cheech stimuli. Compared with clean speech, Cheech-modified speech showed slightly poorer recognition performance as SNR decreased and somewhat higher perceived effort overall. Yet, Cheech was highly effective at evoking auditory responses from the brainstem (auditory brainstem response, ABR) through the cortex (including middle- and late-latency responses, MLR and LLR) even with <5 minutes listening time per condition. Neural responses showed reduced amplitudes and prolonged latencies as SNR decreased. In general, ABR latencies and wave I amplitudes were associated with speech-in-noise recognition performance, whereas cortical responses (MLR Na, Nb, and LLR P1) were associated with subjective workload. These findings show that Cheech-modified speech preserves intelligibility while yielding robust, multilevel neural recordings during sentence perception, offering a promising approach to examine hierarchical auditory processing under ecologically relevant speech-in-noise conditions.

Cisplatin is a potent, broad-spectrum chemotherapeutic agent widely used against multiple malignancies, yet its clinical utility is substantially restricted by dose-limiting adverse effects dominated by nephrotoxicity and ototoxicity. Although cisplatin-induced ototoxicity has been recognized for decades, the precise molecular cascades triggering cisplatin-evoked permanent hearing impairment remain incompletely defined. Therefore, in-depth investigation into the molecular mechanisms of cisplatin-induced ototoxicity and the development of effective prevention strategies represent key scientific issues. Herein, we constructed a chronic cisplatin-exposed animal model and verified prominent pathological features encompassing excessive DNA damage and mitochondrial dysfunction, paralleled by marked downregulation of the DNA repair enzyme MUTYH. Follow-up in vitro assays validated that overexpression of MUTYH significantly alleviated cisplatin-induced ROS accumulation, cell apoptosis, and DNA damage, suggesting that downregulation of MUTYH may be a key molecular event in cisplatin-induced ototoxicity. Notably, exogenous short-chain fatty acid supplementation robustly rescued cisplatin-induced sensory cell loss and hearing loss, concurrent with restored MUTYH abundance. Collectively, our findings reveal that short-chain fatty acids protect cochlear sensory cells from cisplatin-initiated DNA damage via sustaining MUTYH expression, thereby preserving auditory function. As indispensable gut microbial metabolites in humans, short-chain fatty acids supplementation holds promising translational potential as a clinically viable regimen to counteract cisplatin-associated ototoxicity.

Mammalian cochlear hair cells convert acoustic stimuli into electrical signals, which are relayed to the central auditory pathway via auditory neurons. Progressive loss of hair cells and their synapses is a characteristic of age‐related hearing loss (ARHL), but the underlying mechanisms remain poorly understood. In this study, we tested the hypothesis that hair cell physiological properties change with age in CBA/CaJ mice, a strain known for its slow ARHL progression. We found that hair cell size began to decrease from 10 months of age, well before detectable increase in hearing thresholds from auditory brainstem responses. This structural change was associated with a significant decrease in the size of the basolateral membrane current, in particular that carried by the large conductance calcium‐activated potassium (BK) channel currents ( I K,f ) in the apical inner hair cells (IHCs). However, the size of the mechanoelectrical transducer (MET) current measured in the IHCs remained unaffected at least up to 22 months of age. Our results provide clear evidence of an early change in the physiological properties of apical IHCs with age, which precedes measurable hearing loss, suggesting that these cellular deficits might define a distinct pathological route in the CBA/CaJ mice.

Introduction The mitochondrial calcium uniporter (MCU) mediates mitochondrial Ca 2⁺ uptake, but its involvement in cisplatin-induced ototoxicity remains poorly understood. We investigated MCU expression and its association with cisplatin-induced injury in mouse cochlear basilar membranes and HEI-OC1 cells. Methods MCU protein abundance and localization were assessed by Western blotting and immunofluorescence. MCU expression was genetically reduced by lentiviral knockdown, and Ru360 was used as a pharmacological intervention. Apoptosis-related proteins and transcriptomic changes were evaluated. An acute cisplatin-induced ototoxicity model was established in C57BL/6 mice and assessed using auditory brainstem response (ABR) measurements and outer hair cell counts. Results Cisplatin increased MCU expression and reduced SERCA2 expression; the cisplatin-induced increase in MCU was partially reversed by BAPTA-AM and the endoplasmic reticulum stress inhibitor 4-PBA. MCU knockdown did not affect basal cell viability but attenuated cisplatin-induced reductions in viability, TUNEL positivity, and cleaved caspase-3. It was also associated with increased SERCA2 and decreased IP3R, GRP75, and VDAC1 expression. RNA sequencing identified differentially expressed genes enriched in autophagy-related processes and mTOR signaling. MCU knockdown was associated with increased PI3K/AKT/mTOR signaling and changes in Beclin1, LC3B-II, and p62. Ru360 cotreatment partially reproduced the protective phenotype in vitro and was associated with attenuated ABR threshold elevation at selected frequencies and reduced outer hair cell loss in vivo . Discussion These findings support an association between MCU-related signaling, PI3K/AKT/mTOR pathway activation, altered autophagy-related markers, and reduced cisplatin-induced cochlear injury.

Understanding the molecular basis of hair cell function is essential for elucidating inner ear physiology and developing therapies for auditory–vestibular disorders. Here, we identify acyl-CoA binding domain-containing 7 ( Acbd7 ) as a hair cell-specific gene critical for sensory maintenance. Single-cell transcriptomics of mouse cochlear organoids revealed Acbd7 as a top hair cell-enriched transcript, with its spatiotemporal expression confirmed from embryonic development through adulthood in both auditory and vestibular hair cells. Acbd7 ‑deficient mice exhibited pronounced hair cell degeneration, characterized by synaptic defects and diminished calcium currents in inner hair cells and loss of outer hair cells. Transcriptomic and proteomic analyses linked Acbd7 to the regulation of Ca 2+ signaling and fatty acid metabolism pathways. Our findings establish Acbd7 as a critical regulator of Ca 2+ homeostasis and functional integrity in hair cells, thereby elucidating a key mechanism by which a fatty acid metabolism factor sustains hair cell function and providing potential therapeutic targets for inner ear disorders.

The detection of unexpected sounds, or auditory deviance detection, is thought to be achieved by comparing prediction signals and sensory inputs in the auditory cortex. This process is markedly impaired in patients with schizophrenia. However, the local circuit properties underlying deviance detection, together with their dysfunction in schizophrenia-related conditions, remain poorly understood. We used two-photon calcium imaging to monitor the population activity of cortical neurons during auditory deviance detection. The deviance-detecting component was predominant in layer 2/3 neurons of the higher-order auditory cortex. The deviance-detecting cells were spatially clustered, exhibited robust synchronization, and constitutively expressed immediate-early genes. In the Del(1.5 megabase)/+ mouse model of 22q11.2 deletion syndrome, a model of schizophrenia, deviance-detecting activity in the upper-layer network was disrupted, accompanied by dysregulated gene expression and selective loss of dendritic spines in immediate-early gene–positive neurons. Our findings support the hypothesis that ensemble activation of this neuronal subpopulation amplifies unexpected inputs, driving error signals that propagate to higher-order cortical areas.

Cochlear damage triggers compensatory primary auditory cortex (A1) plasticity that amplifies responses to residual sensory inputs, thereby contributing to the restoration of both cortical responsiveness to sound and perceptual sound detection threshold. However, this adaptation can become maladaptive, producing neuronal hyperactivity that contributes to tinnitus and hyperacusis. The neuromodulatory mechanisms governing these adaptive and maladaptive changes remain unknown. Here, we demonstrate that noise-induced cochlear injury triggers bidirectional synaptic zinc signaling plasticity that potentiates activity in excitatory principal neurons and parvalbumin-expressing interneurons, while suppressing activity in somatostatin-expressing interneurons. These cell-type-specific effects of synaptic zinc plasticity contribute to restoring A1 responsiveness to sound and perceptual detection thresholds, while being necessary for neural hyperactivity. Together, our findings establish synaptic zinc as a pivotal neuromodulator that shapes both adaptive and maladaptive cortical plasticity and identify a promising therapeutic target for improving perceptual recovery after cochlear damage and mitigating tinnitus and hyperacusis.

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 impairing endogenous nitric oxide (NO) biocatalysis. 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 restoring endogenous NO biocatalysis. The resulting nanoparticles exhibited an average diameter of approximately 169.9 nm, a positive surface charge (+ 17.18 mV), sustained ROS-responsive drug release, excellent biocompatibility, and prolonged cochlear retention 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, restored eNOS/iNOS-associated NO biocatalytic homeostasis, improved endothelial functional phenotypes, and protected HEI-OC1 cells against oxidative injury. In a C57BL/6 mouse model of NIHL, AD 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. Mechanistically, AD remodeled the pathological cochlear microenvironment through coordinated suppression of ROS/NF-κB-mediated inflammatory activation and restoration of endogenous NO biocatalysis, thereby interrupting the reciprocal amplification between inflammatory dysregulation and vascular 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 therapeutic approach for the treatment of noise-induced hearing loss.