Introduction
Inner ear disorders, particularly sensorineural hearing loss (SNHL), pose substantial therapeutic challenges due to the intricate anatomy of the cochlea and presence of physiological barriers such as the blood–labyrinth barrier [1,2]. These barriers severely restrict the penetration of systemically administered drugs into the cochlear fluids, often resulting in subtherapeutic concentrations at the target site and limited clinical efficacy.
As alternatives to systemic administration, intratympanic and intracochlear delivery methods have been explored, enabling more localized and direct access to the inner ear. Various delivery platforms have been employed to enhance the efficiency of drug delivery in localized inner ear therapy, including hydrogels such as poloxamer, polymeric nanoparticles, solid lipid nanoparticles, liposomes, and superparamagnetic iron oxide nanoparticles (SPIONs) [3]. Among the various delivery platforms under investigation, nanoparticles have received considerable attention. Initially developed and widely used in oncology—for example, to improve the pharmacokinetics and targeting of chemotherapeutic agents—nanoparticles are now undergoing active adaptation for inner ear applications [4,5].
A major advantage of nanoparticles is their versatility. Through surface functionalization, they can be engineered to perform a variety of tasks, including targeting specific cell types, responding to environmental stimuli (e.g., pH, redox, enzymes, or light), and enabling controlled drug release. These functionalization strategies, which have been refined in other fields, are increasingly undergoing translation into inner ear drug-delivery systems [6,7].
This review focuses on the functionalization strategies of various nanoparticles applied to inner ear drug delivery. We summarize the current progress in the field, highlight emerging technologies, and discuss their potential for clinical translation.
Active Targeting
Cell-specific targeting is emerging as a particularly promising approach for inner ear therapeutics. By conjugating nanoparticles with ligands or peptides that recognize markers unique to cochlear cells, researchers can improve both the precision and efficacy of drug delivery.
Prestin
For targeted nanoparticle-based drug delivery in the inner ear, it is essential to identify a suitable molecular target that meets several biological and anatomical criteria. First, the target protein must be selectively or predominantly expressed in the specific cell type implicated in SNHL. Second, the target cell population should be functionally relevant to the pathology and recovery of the inner ear; specifically, restoration or protection of these cells should meaningfully contribute to hearing preservation or restoration. Third, the target must be spatially accessible to therapeutic agents delivered into the perilymphatic space, particularly via the intratympanic or intracochlear routes.
Because tight junctions separate the perilymph and endolymph compartments [8], nanoparticles introduced into the perilymph primarily interact with the basolateral surfaces of cells exposed to this space. Therefore, an ideal target protein should be expressed on the membrane surface of cells directly facing the perilymph. Proteins located intracellularly or in compartments sequestered from perilymph exposure are less viable for direct targeting.
Prestin, a motor protein encoded by the SLC26A5 gene, fulfills all of these conditions and is currently considered one of the most promising molecular targets for cochlear-specific drug delivery [9]. Prestin is exclusively expressed in outer hair cells (OHCs) of the cochlea and is not found in other tissues or inner ear cell types. OHCs play a critical role in cochlear amplification and sensitivity; they are the primary site of damage in various forms of SNHL, including noise-induced and ototoxic hearing loss [10,11].
Importantly, prestin is located on the lateral membrane of OHCs, which is exposed to the perilymph. This localization allows nanoparticles delivered via the round window membrane (RWM) or cochleostomy to access and bind to it [12]. Consequently, prestin-targeting strategies can selectively direct therapeutic agents to OHCs while sparing non-target cells, enhancing both efficacy and safety.
Given its expression specificity, pathological relevance, and perilymphatic accessibility, prestin represents a compelling target for cochlear drug delivery.
Prestin-targeted nanoparticles
In 2012, a considerable step was taken toward cell-specific drug delivery within the cochlea through the identification of two 12-mer peptides, A665 and A666, which exhibit high affinity for prestin [13]. Their selective binding has been validated via flow cytometry. When conjugated to polyethylene glycol (PEG)-b-PCL polymersomes, both A665 and A666 facilitate targeted delivery to OHCs in cochlear explant models, confirming their potential for precise cochlear drug delivery [13].
An in vivo study has demonstrated the therapeutic efficacy of A666-conjugated nanoparticles encapsulating dexamethasone. These nanoparticles were applied to the round window niche in an animal model of cisplatin-induced hearing loss, resulting in a significant protective effect and clear evidence of active targeting to OHCs (Fig. 1) [14]. In another study, researchers developed a modified version of prestin-targeting peptide 1, which included an additional eight amino acids at the C-terminal end to facilitate conjugation with therapeutic agents. This peptide was incorporated into a nanohydrogel system encapsulating a c-Jun N-terminal kinase (JNK) inhibitor, D-JNKi-1. When administered in a noise-induced hearing loss model, the system demonstrated significant preservation of hearing function and effective delivery to the target cells [15].
Moreover, ongoing efforts to optimize prestin-targeting strategies have led to the development of additional peptide variants, such as LS19 and prestin-targeting peptide 2 [16,17]. These modified peptides have also exhibited enhanced binding affinity and specificity for OHCs, further supporting the feasibility of prestin-targeted delivery systems as a promising platform for treating SNHL.
Stimuli-Responsive Strategies
The middle ear cavity, situated between the tympanic membrane and the inner ear, serves as an accessible and effective route for local drug administration, particularly through intratympanic injection. In recent years, there has been increasing interest in the development of stimuli-responsive drug delivery systems designed to improve the retention, penetration, and controlled release of therapeutics—especially nanoparticles—targeting the inner ear.
These systems, which may respond to heat, light, pH, or reactive oxygen species (ROS), represent a promising frontier in the treatment of SNHL [18]. By enhancing local drug retention and enabling on-demand or site-specific release, they offer more precise, efficient, and patient-tailored therapies.
Intrinsic stimuli-responsive delivery system
Among the various thermoresponsive hydrogels investigated for local drug delivery, poloxamer 407 is one of the most extensively studied and clinically advanced [19]. This nonionic triblock copolymer is composed of a central hydrophobic block of polypropylene glycol flanked by hydrophilic PEG chains. Due to its amphiphilic structure, it forms micelles in aqueous environments and undergoes a reversible sol-to-gel transition near body temperature, making it particularly well-suited for injectable formulations (Fig. 2) [20,21].
Because of its favorable biocompatibility, injectability, and capacity to form an in situ gel depot, poloxamer 407 has been widely utilized as a vehicle for sustained drug release. It is recognized by the United States Food and Drug Administration as a safe pharmaceutical excipient and has been incorporated into ophthalmic, topical, and parenteral drug products [20].
In the context of otologic applications, poloxamer 407 has been incorporated into clinical trial–stage intratympanic therapeutics to enhance drug retention in the middle ear and promote effective diffusion into the inner ear. Notable examples include FX-322 (Frequency Therapeutics, Inc.), a formulation designed to stimulate cochlear hair cell regeneration using small molecules, and OTO-104 (Otonomy, Inc.), a sustained-release dexamethasone gel evaluated for Ménière’s disease and cisplatin-induced ototoxicity [22]. These examples highlight the utility of poloxamer-based hydrogels in overcoming pharmacokinetic barriers and improving therapeutic outcomes in inner ear disorders.
In addition to poloxamer 407, a variety of thermosensitive hydrogels based on both synthetic and natural polymers have been developed for drug-delivery applications. Recently, chitosan-based hydrogels have also been explored for use in the inner ear. In particular, hexanoyl glycol chitosan has been synthesized and evaluated as an amphiphilic thermogel with a sol–gel transition temperature around 32°C. It functions both as a solubilizing agent and an injectable carrier for the intratympanic delivery of dexamethasone. As a prodrug-blend hydrogel, it controls release characteristics, maintains therapeutic levels of the drug in the inner ear for up to 7 days, and undergoes complete self-degradation within 1 month. In a guinea pig model of noise-induced hearing loss, this system led to significant hearing recovery and OHC preservation, highlighting its therapeutic potential for inner ear disorders [23].
Another example was reported by Zhao, et al. [24], involving the use of ROS-responsive nanoparticles. ROS play a key pathogenic role in SNHL, including noise-induced hearing loss. The cited study employed poly(propylene sulfide)120, a polymer that actively scavenges ROS and undergoes oxidation to form poly(propylene sulfoxide)120. This transformation triggered disintegration of the nanoparticle structure and induced rapid release of the encapsulated drug berberine, which possesses both anti-inflammatory and antioxidant properties (Fig. 3) [24].
Extrinsic stimuli-responsive delivery system
One of the earliest extrinsic strategies explored for inner ear drug delivery involved the use of magnetic fields to actively propel drug-loaded nanoparticles from the middle ear into the cochlea [25-28]. Conventional therapeutics administered to the middle ear rely on passive diffusion across the RWM, driven solely by concentration gradients. To overcome this limitation, researchers have developed systems in which magnetic nanoparticles (MNPs), loaded with therapeutic agents, are guided toward the cochlea by applying an external magnetic field. More recently, Julia Martín, et al. [29] reported a targeted delivery platform utilizing folic acid–functionalized MNPs (MNPs@FA) to carry the anti-inflammatory drug diclofenac (Dfc). MNPs@FA can penetrate the RWM, supporting their potential to overcome the primary barrier to SNHL therapy. These findings represent a meaningful step toward future in vivo applications and clinical translation.
Light-responsive delivery systems have emerged as another promising extrinsic approach. To achieve precise spatiotemporal control over drug release, near-infrared (NIR) light has been investigated due to its deep tissue penetration and low phototoxicity [30,31]. A recent study developed a nanocomposite system composed of gold nanorods (AuNRs) encapsulated in a mesoporous silica shell that functions as a drug reservoir for corticosteroids. Upon NIR irradiation through the tympanic membrane, the AuNRs convert light into localized heat via photothermal conversion, triggering controlled release of the encapsulated drug. Furthermore, the system incorporates saponin, an amphiphilic molecule that enhances RWM permeability by disrupting its lipid bilayer structure. This combined mechanism enables efficient dexamethasone delivery into the inner ear and produces robust therapeutic effects in a cisplatin-induced hearing loss model, including OHC preservation and synaptic ribbon protection, even at low steroid doses (Fig. 4) [31].
Enhanced Penetration and Permeability
Improvements to nanoparticle penetration across the RWM and enhancement of cellular uptake within the cochlea are critical for efforts to achieve effective inner ear drug delivery. One widely studied approach is surface functionalization, in which nanoparticles are modified with PEG, cell-penetrating peptides (CPPs), or positively charged moieties to increase their permeability, tissue distribution, and cellular internalization [32,33].
Yoon, et al. [32] developed a drug-delivery system using nanoparticles conjugated with oligoarginine (Arg8), a well-known CPP. Their formulation, PHEA-g-C18-Arg8, significantly enhanced cellular uptake in HEI-OC1 cells and inner ear tissues after intratympanic administration. Notably, this system also demonstrated potential for gene delivery to the inner ear. Building on this approach, Yang, et al. [33] investigated phospholipid-based nanoparticles with various surface charges (neutral, anionic, cationic, and PEGylated cationic [Cat-PEG]) for the delivery of dexamethasone. Among tested formulations, Cat-PEG nanoparticles exhibited the most favorable combination of RWM permeability, cochlear tissue uptake, and biocompatibility, leading to superior drug penetration and improved hearing preservation in a mouse model of ototoxicity.
These findings underscore the importance of surface engineering in the rational design of inner-ear drug-delivery systems. Functionalization strategies such as PEGylation, CPP attachment, and charge modulation hold considerable potential to overcome anatomical barriers and improve therapeutic outcomes in SNHL.
Conclusion
Advances in nanotechnology have opened new avenues for overcoming the unique anatomical and physiological barriers of the inner ear. Among various strategies, surface functionalization of nanoparticles has emerged as a critical design element to improve the precision, efficacy, and safety of drug-delivery systems. This review highlights three major approaches: active targeting, particularly via prestin-specific ligands for OHC selectivity; stimuli-responsive systems, which utilize internal or external cues for spatiotemporal control of drug release; and enhanced permeability techniques, including PEGylation, cationic surface modifications, and the use of CPPs to promote transport across the RWM and cellular internalization.
These strategies, many of which are adapted from advances in oncology and other biomedical fields, have shown promising preclinical results in inner ear applications. However, the inner ear toxicity of new materials—including their inherent ototoxicity, potential to induce inflammation, and accumulation within the cochlea—and, in particular, their long-term safety in the inner ear must also be thoroughly investigated [34]. Continued interdisciplinary efforts integrating molecular biology, materials science, and otologic research are crucial for translation of these innovative delivery systems into clinically viable therapies.
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