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INTRODUCTION
Onychomycosis, which causes 20-40% of all illnesses that are referred to as onychopathies and roughly 30% of cutaneous mycotic infections, is a widespread illness that affects 5.5% of people globally (Akhter et al., 2024). Fingernail onychomycosis can cause pain, discomfort, and loss or impairment of tactile functions. Toenail dystrophy can make it difficult to walk, exercise, or wear properly fitting shoes. Furthermore, onychomycosis causes negative physical and psychological repercussions (Hadi et al., 2024). Yeasts, which used to be thought of as pollutants, are now more widely acknowledged as pathogens in fingernail diseases. Candida parapsilosis, Candida tropicalis, and Candida krusei are responsible for the remaining 70% of cases, with Candida albicans accounting for the balance. As seen among housewives, farmers, and fishermen, long-term exposure to dampness and chemicals, such as detergents, as well as compromised local immunity resulting from trauma, leads to CO, together with Candida paronychia. A main or secondary disease can be Candida. In cases of severe immune suppression, its function as a primary pathogen is almost always apparent in conditions like HIV infection and Chronic Mucocutaneous Candidiasis (CMC). On the other hand, secondary invasion by Candida occurs at the nail complex in cases of PVD, malnourishment, and compromised local immunity. It is well known that the keratin in nail polish creates an ideal environment for the growth of virulent Candida strains (Alessandrini et al., 2020). Clinical signs of onychomycosis include Distal and Lateral Subungual Onychomycosis (DLSO), Proximal Subungual Onychomycosis (PSO), Superficial White Onychomycosis (SWO), Endonyx, and Total Dystrophic Onychomycosis (TDO).
Lateral and Distal Subungual Onychomycosis
The most common medical condition associated with moving the fingers and toenails together is DLSO. The yeast enters through the lateral and distal deep nail cavities, extends closest toward the developing nail stream after invading the horny layer of the hyponychium and/or nail tissue, and then passes through the opaque underside of the nail plate. Clinical manifestations include subungual hyperkeratosis and onycholysis. It serves as a mycotic reservoir for fungal growth. T. rubrum is the most prevalent causative species, followed by T. tonsurans, T. mentagrophytes, and Epidermophyton floccosum. rubrum causes "one hand, two feet" tinea syndrome, a unique clinical pattern in DLSO in which the fungus spreads from the palmar and plantar surfaces of the hands and feet (Pereira-Leite et al., 2025). T. mentagrophytes var. interdigitale causes chronic dermatophytosis syndrome, which begins as tiny, 1 mm-sized plantar vesicles and collarettes over the soles, which are home to a large number of hyphae (Gupta et al., 2023).
Nanoemulsions
The nanoemulsion is an innovative drug delivery system that has gained significant importance in recent years due to its ability to address the challenges of traditional formulations, particularly for complicated infections such as onychomycosis (Bencherif et al., 2009). They are colloidal dispersions comprising two immiscible phases, often water and oil, stabilised by co-surfactants and surfactants, and which exist in a droplet size range of 20 to 200 nanometres (Mishra et al., 2019). In contrast to macroemulsions, nanoemulsions are highly kinetically stable, transparent, and feature excellent droplet sizes, which increase drug solubility, stability, and the ability to penetrate biological barriers (ElSherif et al., 2017). Their special features make them very useful for topical use, as enhanced permeation is required. The issue of targeting the delivery of antifungal agents to within the dense keratinised plate of the nail and retaining high concentrations of drugs at sites of infection for extended durations, where the efficacy of therapy is enhanced, is dual beneficial in the case of onychomycosis, particularly with nanoemulsions (See in Table 1) (Chaurasia, 2024).
| Group | Causative Organisms | Key Features | Role in Onychomycosis | References |
|---|---|---|---|---|
| Dermatophytes | Trichophyton rubrum, Trichophyton mentagrophytes | Keratinophilic fungi invade keratinised tissues (nail, skin, hair). | The most common cause (60-70% of cases) is usually chronic, slowly progressive infections. | (Westerberg et al., 2013a) |
| Yeasts | Candida albicans, Candida parapsilosis | Opportunistic fungi are part of normal flora infections favoured by immunosuppression or chronic moisture. | Responsible for 20-25% of cases; more frequent in fingernails, often with paronychia. | (Westerberg et al., 2013a) |
| Non-Dermatophyte Moulds (NDMs) | Scopulariopsis brevicaulis Fusarium species Aspergillus species | Environmental saprophytes; not primarily Keratinophilic but can colonise or infect damaged nails. | Cause 10-15% of cases; often linked to trauma, pre-existing nail disease, or immunosuppression. | (Westerberg et al., 2013b) |
Pathophysiology and Challenges in Treating Onychomycosis
Pathophysiology of Onychomycosis
Is a chronic mycological contamination affecting the nail unit, including the nail dish, nail bed, and surrounding tissues. The development of onychomycosis is closely associated with both the pathogenic characteristics of fungi and the complex structure of the nail unit (Pugazhendhi et al., 2020). The nail plate acts as a strong protective barrier because it is composed mainly of densely packed keratin. This keratinized structure restricts the penetration of therapeutic agents and also limits immune defence mechanisms (Leung et al., 2019; Pabale et al., 2022). These enzymes destroy the nail matrix and cause structural damage, including thickening, brittleness, discolouration, and a distorted nail plate. The most common cause of onychomycosis is dermatophytes (primarily Trichophyton rubrum and Trichophyton mentagrophytes), which account for most cases worldwide (Atram et al., 2022) (shown in Figure 1).
Challenges in Treating Onychomycosis
The development of antifungal therapy for onychomycosis remains challenging due to physiological and pharmacological barriers. The nail plate is a compact, closely packed keratin fiber that serves as an effective barrier to drug penetration. This restricts the penetration of topical antifungal agents into the infected nail bed, resulting in subtherapeutic drug levels at the site of infection. Nail growth is very slow, which increases the treatment time. The growth rate of toenails is about 1-2 mm each month, so it can take 12-18 months for the whole nail to be replaced, which is one reason the course of treatment is quite long. A large range of causative fungi may also develop as biofilms in the nail structure. Biofilms also shield fungal cells from antifungal agents and the immune system, leading to persistent infections and treatment failure.
Components and Formulation Strategies
The nanoemulsion formulation will need three key components: the oil phase, the surfactant/co-surfactant system, and the aqueous phase (Winnicka et al., 2012). Lipophilic antifungal agents are transported through the oil phase, and this increases their solubility and bioavailability. Advanced topical therapies for onychomycosis: Nanoemulsions (NEs) and nanoemulgels are excellent methods for treating onychomycosis, using submicron-sized droplets that can improve drug solubility and absorption across the keratinised nail plate. These systems, which incorporate oils, surfactants, and gelling agents, provide superior drug concentration and sustained release compared with conventional therapies, thereby reducing systemic toxicity (See Table 2) (Prajapati et al., 2025).
| Component | Examples | Role in Formulation |
|---|---|---|
| Oil Phase | Medium-chain triglycerides, isopropyl myristate, essential oils (e.g., tea tree oil) | Enhances solubility and bioavailability of lipophilic drugs; influences droplet size and drug release rate. |
| Surfactant | Tween 80, Span 20, Cremophor EL | Reduces surface and interfacial tension; promotes uniform mixing of oil and water; improves solubility of poorly water-soluble drugs. |
| Co-surfactant | Ethanol, propylene glycol, polyethene glycol | Further reduces interfacial tension; increases flexibility and stability of the interfacial film. |
| Aqueous Phase | Purified water, buffer solutions | Provides a medium for hydrophilic excipients; maintains pH for formulation stability. |
| Penetration Enhancers | Urea, thioglycolic acid, salicylic acid | Softens and hydrates the nail plate; enhances drug permeability and bioavailability. |
| Stabilisers/Antioxidants | Vitamin E, Butylated Hydroxytoluene (BHT) | Prevents phase separation, aggregation, and drug precipitation; prolongs shelf-life and maintains stability. |
METHODS OF PREPARATION OF NANOEMULSIONS
With droplets typically between 20 and 200 nm, nanoemulsions are thermodynamically or kinetically stable colloidal dispersions composed of oil, water, a detergent, and, frequently, a co-surfactant. Both high-energy and low-energy emulsification methods can be used to prepare them, depending on the formulation requirements and the physicochemical properties of the components. These preparation methods influence droplet size, stability, drug loading capacity, and permeation efficiency. The commonly used preparation techniques are summarised below.
High-Energy Emulsification Methods
These techniques use mechanical devices to generate intense disruptive forces that break coarse emulsions into nano-sized droplets.
High-Pressure Homogenization
This technique involves applying extremely high pressure while passing the coarse emulsion through a small opening (500-5000 psi). The intense shear stress, cavitation, and turbulence reduce droplet size to the nanometre range, resulting in a uniform and stable nanoemulsion. Ultrasonication uses ultrasonic waves generated by a probe sonicator. The audio cavitation produced during sonication causes microbubbles to form and collapse, breaking larger droplets into smaller nanoscale droplets. Microfluidization: This technique employs a microfluidizer in which two streams of coarse emulsion collide at high velocity in microchannels. The strong shear forces and impact reduce droplet size, producing highly stable nanoemulsions with a narrow size distribution.
Low-Energy Emulsification Methods
Low-energy methods count on the impulsive formation of nanoemulsions through changes in system composition or temperature. Phase Inversion Temperature (PIT) Method. This method uses temperature-induced phase inversion of non-ionic surfactants. When the temperature changes, the surfactant's affinity for the oil and water phases shifts, leading to the formation of nanosized droplets. In the Stage Inversion Arrangement (PIC) method, the regular addition of water to a mixture of oil, surfactant, and co-surfactant leads to phase inversion and the spontaneous formation of nanoemulsions. The spontaneous emulsification method involves mixing oil, surfactant, and co-surfactant with an aqueous phase under gentle stirring.
Nanoemulsions can be prepared by means of either high-energy or low-energy methods (see Table 3).
| Method | Type | Principle | Advantages | Limitations |
|---|---|---|---|---|
| High-Pressure Homogenization | High-energy | Uses high pressure to force coarse emulsion through a narrow gap, breaking droplets into nanoscale sizes. | Produces uniform droplets; scalable for industrial production. | Requires expensive equipment; generates heat, which may degrade sensitive drugs. |
| Microfluidization | High-energy | Employs microchannels where two streams collide at high velocity, creating nanosized droplets. | High stability; excellent droplet size control. | High cost; energy-intensive process. |
| Ultrasonication | High-energy | Utilises ultrasonic waves to create cavitation forces that reduce droplet size. | Simple, cost-effective for small-scale production; good for heat-sensitive drugs. | Limited scalability; potential contamination from probe erosion. |
| Spontaneous Emulsification | Low-energy | Relies on diffusion of oil into the aqueous phase under controlled conditions, leading to droplet formation. | Easy to perform; no special equipment needed. | Droplet size may be larger and less stable than high-energy methods. |
| Phase Inversion Temperature (PIT) | Low-energy | Emulsion formation occurs by changing temperature, which alters surfactant solubility and causes phase inversion. | Produces fine droplets; energy efficient. | Limited to non-ionic surfactants; sensitive to temperature variations. |
| Solvent Evaporation/Diffusion | Low-energy | Organic solvent containing oil phase diffuses/evaporates, leading to nanosized droplets in the aqueous medium. | Good for encapsulating lipophilic drugs; simple procedure. | Requires removal of organic solvents; potential residual toxicity. |
Mechanism of Drug Delivery Through the Nail Plate
The success of antifungal treatment in onychomycosis is, in the most significant part (Figure 2), caused by the capacity of the medication to penetrate the dense and keratinised nail plate to reach the infection area under the nail plate (Sherje et al., 2018). The nail plate, due to its strong, non-absorbent nature, presents significant challenges to drug penetration into the skin; hence, conventional topical medications are less useful (Sarode et al., 2024; Jafari et al., 2021). Nanoemulsions, owing to their small droplet size and engineered surface features, have demonstrated the potential to overcome these obstacles by promoting more effective drug delivery through the nail plate (Kumar et al., 2011). There are three main routes through which drugs penetrate the nail: the interpleural, intercellular, and transcellular pathways. The transcellular path: Drugs enter the nail plate directly through keratinised cells (Langaroudi et al., 2019).
The nanoemulsion droplet size (nanoscale) is also significant in improving transdermal drug delivery (Khan et al., 2024). Droplets with diameters between 20 and 200 nm would have high surface-to-volume ratios. Smaller droplets also spread more widely, resulting in a more even distribution and longer contact with the nail plate, which is paramount for drug release (Padrilah et al., 2024).
Enhanced Efficacy and Reduced Toxicity
The key advantage of nanoemulsions is that they allow the dramatic enhancement of the efficacy of antifungal drugs (Shah et al., 2012). The droplets that are too small will enable drugs to enter the depth of the layers that include the nail bed, which docks a colony of the fungus, and this gives close contact with the surface of the nail. The outcome of this further penetration is greater local drug dosing, which helps more efficiently eradicate infections, including Trichophyton rubrum and Candida species (Shahbaz, n.d.; Song et al., 2020).
Stability, Scalability, and Patient Compliance
Small emulsions have high kinetic stability, which does not permit the degradation and phase separation of drugs. Alternatively, due to their stability, the substances have an extended shelf life and can therefore be easily marketed (Akhter et al., 2024). They are also simple to administer due to their non-greasy texture and low viscosity, which increases patient compliance, which is crucial in the long-term management of onychomycosis (Gupta et al., 2010). From a production standpoint, nanoemulsions can be sized using standard high-energy techniques. Tiny fluidisation to guarantee a constant degree of product quality (Daphne Nguyen et al., 2025).
Formulation Challenges
Although there are many potential applications for nanoemulsions, there are a number of barriers to their widespread adoption (Kabanov et al., 2009). Even if nanoemulsions are kinetically stable, phase separation may still take place under difficult storage circumstances, which is a serious problem. The choice of surfactants and co-surfactants is critical, as they should avoid irritating the nail or surrounding skin while not irritating the skin (Bhaskar et al., 2025).
FUTURE PROSPECTS AND LIMITATIONS
Because they can enhance the solubility of medications, promote deeper penetration into the nails, and enhance antifungal properties, nanoemulsions have high potential for the treatment of onychomycosis. In the future, these studies are likely to focus on the development of multifunctional nanoemulsions containing antifungal drugs either in combination with stimuli-responsive carriers or with sustained-release carriers or with natural bioactive components for longer activity and reduced number of doses.
Marketed Antifungal Formulations for Onychomycosis
The marked preparation and patent are seen in Table 4.
| Brand Name | Active Drug | Dosage Form | Concentration | Manufacturer | Key Features |
|---|---|---|---|---|---|
| Efinaconazole (Jublia®) | Efinaconazole | Topical solution | 10% | Bausch Health | Low surface tension improves penetration into the nail plate. |
| Tavaborole (Kerydin®) | Tavaborole | Topical solution | 5% | Sandoz | Boron-based antifungal with good nail permeability. |
| Ciclopirox (Penlac®) | Ciclopirox | Nail lacquer | 8% | Sanofi | Broad-spectrum antifungal used for mild infections. |
| Amorolfine (Loceryl®) | Amorolfine | Nail lacquer | 5% | Galderma | Inhibits fungal sterol biosynthesis. |
| Terbinafine (Lamisil®) | Terbinafine | Oral tablet / topical | 250 mg | Novartis | Systemic therapy has a high cure rate. |
| Itraconazole (Sporanox®) | Itraconazole | Oral capsule | 100 mg | Janssen | Pulse therapy is commonly used in severe infections. |
Recent Nano-Drug Delivery Systems (Nano-DDS) Investigated for Onychomycosis
In vitro and in vivo studies on DDS related to Onychomycosis are shown in Table 5.
| Drug | Nano-DDS Type | Key Components | Study Type | Major Findings | References |
|---|---|---|---|---|---|
| Amorolfine | Solid Lipid Nanoparticles (SLN) | Stearic acid, bile salts | In vitro and ex vivo | 1.6-fold higher nail permeation and improved antifungal activity. | Ahmed et al., 2025 |
| Voriconazole | Nanostructured Lipid Carriers (NLC) | Solid + liquid lipids | Ex vivo permeation | Higher drug retention in nail models compared to free drug. | Rocha et al., |
| Terbinafine | Liposomal film formulation | Phospholipids | In vivo study | Improved antifungal activity and sustained drug release. | Tuncay et al., |
| Luliconazole | Liposomal nail lacquer | Liposome vesicles + lacquer base | In vitro | Enhanced nail permeation and antifungal activity. | Chouhan et al., |
CONCLUSION
Onychomycosis remains a significant global health problem due to its frequency, its chronicity and its difficult treatment. The thick keratinised nail plate makes it a formidable barrier to the efficacy of standard class antifungal medicine given topically. Oral antifungals are effective; however, they often have systemic adverse effects and long treatment regimens, which control patient adherence and increase the risk of relapse. Furthermore, the rising incidence of medicinal resistance to antifungal drugs makes the treatment of this illness more challenging. Therefore, there is a grave need for innovative ways of drug delivery that can overcome these limitations. These formulations enhance the stability of the drug, solubility and permeability through biological barriers such as the hard nail plate.