A Synergistic Approach to Overcoming the Ungual Barrier: A Review of Hybrid Niosome Micronneedle Systems for Transungual Drug Delivery

Abstract

Hybrid noisome-microneedle(MN) platforms offer a mechanistically synergistic, localized, and potentially high-efficacy strategy to overcome the nail plate’s formidable barrier in onychomycosis and related nail disorders. Microneedles create controlled microchannels through hard keratin while niosomes deposit drug-loaded, penetration-enhancing nanovesicles as in situ reservoirs for sustained release-addressing the principal shortcomings of both oral (systemic toxicity) and topical (insufficient penetration) therapies. Despite compelling ex vivo and emerging in vivo evidence, translation requires advances in nail-specific MN engineering, standardized ungual testing, scalable niosome manufacturing (e.g., microfluidics), and clearer regulatory pathways for combination device–drug products.

Keywords

Hybrid nanosystems; Microneedles; Niosomes; Onychomycosis; Transungual drug delivery; Nail penetration enhancement

Introduction

1.1.  The Ungual Barrier and The Imperative for Advanced Delivery:

Onychomycosis is a prevalent and recalcitrant fungal infection of the nail apparatus, with population-level estimates often spanning 3–8% globally and a burden concentrated in older, diabetic, and immunocompromised populations. While systemic antifungals (notably terbinafine and itraconazole) achieve meaningful mycological and complete cure rates, they carry risks of hepatic injury, drug–drug interactions, and adherence challenges associated with lengthy regimens. Topical lacquers (e.g., ciclopirox, efinaconazole) improve safety but struggle to achieve therapeutic levels across the dense, disulfide–crosslinked nail plate, leading to low cure rates and high recurrence. The hard, minimally hydrated, tightly packed keratin architecture of the nail plate—distinct from the lipid-rich stratum corneum—demands enabling technologies that both bypass and exploit this barrier.^(1-6)

1.2. Onychomycosis: Global Burden and Therapeutic Gaps:

Contemporary clinical syntheses underscore that oral terbinafine remains the most effective monotherapy overall; in large randomized trials and meta-analyses, mycological cure rates commonly range 67-78%, with complete cure around 32-38%, yet real-world results vary and relapse is common. Topical-only strategies require prolonged courses and typically underperform systemic therapy, though newer lacquers and optimized debridement improve outcomes. The persistent efficacy-safety dichotomy motivates localized, barrier-overcoming approaches that concentrate drug in the bed/matrix while minimizing systemic exposure.^(7-10)

1.3. The Synergistic Convergence of Microneedle and Niosomal Technologies:

Microneedles are micro-scale arrays (approximately 100–1000 μm) capable of creating transient conduits through superficial barriers with minimal pain; when adapted for the thicker, harder nail plate, they enable physical poration to deliver drug to subplate targets. Niosomes—vesicular nanocarriers formed from non-ionic surfactants and cholesterol—encapsulate hydrophilic and lipophilic actives, enhance permeation via surfactant–keratin interactions, and provide sustained release. Hybridizing these modalities allows MNs to open nail microchannels and precisely deposit drug-loaded niosomes into the keratin network, where vesicles serve as localized, controlled-release reservoirs that maintain concentrations above MIC for prolonged periods.^(11-14)

1.4. Advantages of Hybrid Systems Over Conventional Approaches:

Compared with oral drugs, hybrid systems offer localized delivery with markedly reduced systemic exposure. Compared with topicals, they bypass the nail barrier and leverage niosomal penetration enhancement and depot effects. Early ex vivo/in vivo studies in onychomycosis models report superior permeation and fungal burden reduction relative to non-porated and non-nano comparators, suggesting improved efficacy with favorable tolerability.⁽¹⁵⁾ 

2. NAIL ANATOMY AND BARRIER PROPERTIES:

The nail plate is a rigid, highly keratinized, low-lipid, low-hydration barrier with extensive disulfide crosslinking. Its compact corneocyte stacking and tortuous aqueous pathways severely limit passive diffusion of most antifungals. Drug movement occurs primarily via intercellular and transkeratin routes; physicochemical tailoring (size, ionization, hydrogen bonding) and barrier modulation (hydration, keratolytics, surfactants) are required for meaningful delivery. Diverse physical enhancers-abrasion, drilling, iontophoresis, laser, and MNs-have been explored to increase transungual flux, with device-based poration providing the most decisive permeability gains when safely executed.^(9,6)

3. MICRONEEDLE TECHNOLOGY:THE PHYSICAL  GATEWAY:

3.1. Classification and Mechanisms:

• Solid MNs: “poke-and-patch” to create channels followed by application of a drug vehicle; simple but susceptible to rapid channel closure and dosing variability.^(14,11)
• Coated MNs: drug layered on needle surfaces, enabling rapid deposition on insertion; limited by surface area and payload.^(3,14)
• Dissolving MNs: drug-laden biodegradable matrices (e.g., PVA, PVP, saccharides) that dissolve post-insertion, eliminating sharps and enabling higher loads.^(11,14)
• Hydrogel-forming MNs: crosslinked networks that swell and facilitate sustained diffusion from a reservoir; suitable for extended dosing with longer wear times.^(14,11)

3.2. Materials and Fabrication:

MN materials include metals (steel, titanium), silicon, ceramics, and polymers (PVA, PVP, carboxymethylcellulose, hyaluronates). Fabrication spans photolithography, micromolding, etching, solvent casting, and increasingly 3D printing each balancing tip sharpness, aspect ratio, and mechanical robustness.^(11,14) 

3.3. Engineering for Optimal Nail Penetration:

Ungual application imposes higher mechanical demands versus skin. Key determinants include:

• Length: often toward the upper micro-scale to traverse significant plate thickness while avoiding bed trauma.
• Geometry: triangular and conical tips reduce insertion force and enhance fracture resistance.
• Array density/interspace: must avoid the “bed-of-nails” effect and excessive force while maximizing channel count for payload delivery.⁽¹¹⁾

Recent preclinical work deploying antifungal-loaded dissolving MNs for onychomycosis demonstrated reduced nail fungal burden and improved local outcomes versus controls, reinforcing feasibility for nail disease.^[15][3]

3.4. Safety and Tolerability Considerations :

While MNs are generally well tolerated in dermatologic use, ungual device design must mitigate risks of tip fracture, pain from deeper penetration, infection through channels, and residual polymer presence for dissolving/hydrogel systems. Clinical-grade designs should integrate insertion force control and fail-safe geometries.^(16,14)

4. NIOSOMES: A VERSATILE NANOCARRIER FOR LOCAL , SUSTAINED DELIVERY.

4.1. Composition and Structure:

Niosomes are bilayer vesicles formed from non-ionic surfactants (Span, Tween) and cholesterol, optionally with charge inducers. Hydrophilic drugs localize in the aqueous core; lipophiles partition in the bilayer. Compared with liposomes, niosomes are cost-efficient, chemically more stable, and amenable to scalable processes^.(12,13)

4.2. Formulation and Preparation:

Conventional methods include thin-film hydration, ether/ethanol injection, sonication, and detergent depletion. Microfluidic mixing has emerged to produce monodisperse, size-controlled vesicles (<200 nm) with improved reproducibility and industrial scalability, addressing batch heterogeneity inherent to bulk methods. PEGylation and compositional tuning (Span/Tween ratios, cholesterol content) adjust rigidity, release, and stability.^(13,17,5)

4.3. Penetration Enhancement and Dermal/ Ungual Relevance:

Non-ionic surfactants perturb intercellular lipid packing and enhance membrane fluidity; niosome deposition increases drug thermodynamic activity at interfaces and hydrates tissue, altogether augmenting penetration. Extensive transdermal literature supports these mechanisms, with growing application to nail where surfactant–keratin interactions and hydration loosen keratin networks.^(18,12)

4.4. Why Niosomes Suit MN Hybrids:

Niosomes provide: high payload versatility, chemical stability during MN processing, depot behavior in MN-made channels, and intrinsic enhancement via surfactants. Their vesicular integrity within nail micro-pores supports sustained local release while limiting systemic exposure.^[12][13][11]

5. THE HYBRID SYSTEM: MECHANISM AND EVIDENCE.

5.1. Poke And Deliver Sequence:

1. MN poration: creation of microchannels through the nail plate.
2. Targeted deposition: MN-mediated placement of drug-loaded niosomes into channels.
3. In situ reservoir: vesicles occupy pores, resist rapid clearance, and stabilize drug.
4. Sustained diffusion: controlled release from vesicles into bed/matrix maintains therapeutic concentrations over extended periods. 

5.2. Synergistic Effects:

The MN component enables barrier traversal; the niosome component ensures prolonged, high local concentrations and active penetration enhancement. Removal of either component diminishes performance—MNs alone yield brief pulses; niosomes alone cannot cross the intact plate efficiently.⁽¹¹⁾

5.3. Ex Vivo and In Vivo Evidence:

• Microporation plus nanoformulations: human nail clipping models show markedly increased permeation when antifungal nanoparticles are applied after poration; nanoparticles fill pores and extend local release.⁽¹¹⁾
• Dissolving MN antifungal systems: in vivo guinea pig onychomycosis models with terbinafine-loaded dissolving MNs significantly reduced nail fungal burden and local inflammation compared with controls.⁽¹⁵⁾
• Clotrimazole coated MN: polymeric coated MNs demonstrate efficient antifungal delivery through keratin barriers and inform transungual use cases.^[3]

Collectively, these studies support the hybrid concept and inform design variables for nail targeting.

5.4. Formulation Considerations:

Key levers include MN geometry, length, and density optimized for nail; niosome size (e.g., 100–300 nm) and polydispersity for pore occupancy; surfactant/cholesterol ratios for stability and release; and integration into gels or dissolving MN matrices to facilitate handling and residence.^(19,5)

6. THERPEUTIC APPLICATIONS WITH EMPHASIS ON ONYCHOMYCOSIS:

6.1. Clinical Significance:

Onychomycosis requires long-term therapy and is characterized by high recurrence and biofilm involvement. Hybrid systems can provide targeted, depot-like antifungal delivery suitable for recalcitrant dermatophyte and non-dermatophyte infections, potentially reducing treatment frequency and improving adherence without systemic lab monitoring.^(1,7)

6.2. Case Exempler: Ciclopirox Olamine Niosomal Gels with MN Pre-Treatment:

Ciclopirox (topical FDA-approved) formulated into niosomal gels (e.g., Span/Tween/cholesterol) improves ungual penetration versus conventional gels; pairing with MN poration further augments delivery and extends local residence, demonstrating activity even against less susceptible Candida species in preclinical assays. Practical gel bases (e.g., Carbopol) facilitate application and occlusion over porated areas.^(19,12)

6.3. Comparative Context Vs. Conventional Therapies:

Systemic terbinafine provides superior cure rates but with systemic risks; topical monotherapy is safer but underperforms due to poor penetration. Adjuvant debridement enhances outcomes with terbinafine. Hybrids aim to approach systemic-level efficacy locally by overcoming permeability limits while preserving safety—bridging the existing dichotomy.^[7][1]

6.4. Additional Nail Indications:

Hybrid MN–niosome platforms may extend to nail psoriasis, chronic paronychia, and bacterial or mixed infections where sustained, localized anti-inflammatory or antimicrobial delivery is advantageous. The broader MN literature supports feasibility for skin inflammatory diseases and localized infections.^(17,14)

7. CHALLENGES AND TRANSALTIONAL PROSPECTS:

7.1. Manufacturing and Scale-Up:

• MNs: repeatable fabrication of long, nail-penetrating yet fracture-resistant MNs; robust tip integrity and consistent dosing remain critical hurdles.
• Niosomes: batch heterogeneity from bulk methods can be mitigated by microfluidic mixing to yield monodisperse, reproducible vesicles suited for scale, with tunable FRR and solvent systems.^[5]
• Combination integration: embedding niosomes within dissolving/hydrogel MN matrices entails compatibility, stability during drying, and maintained mechanical strength.

7.2. Regulatory Landscape:

FDA guidance exists for transdermal/topical systems on product design, manufacturing, and quality, but nail-specific combination MN–nanocarrier systems occupy a less-defined space, straddling device–drug classifications and necessitating robust CMC, biocompatibility, performance, and human factor evidence. Adhesion, dose uniformity, and heat effects that matter for patches offer useful analogs; however, nail-focused standards and validated in vitro models are still evolving.^(2,4) 

7.3. Safety and Biocompatibilty:

Risks include local infection through channels, pain with deeper penetration, and retention of polymer fragments. Long-term fate and local tolerability of residual materials must be characterized. Niosome excipients (non-ionic surfactants) are generally biocompatible; surface modifications (e.g., PEG) and optimized compositions can further reduce irritation and modulate immune responses.^(20,13)

7.4. Market and Health-Economic Context:

The onychomycosis treatment market is large and steadily growing, with 2024 estimates around USD 3.36–4.2 billion and CAGRs ~4–5% through the next decade. Topicals remain the largest and fastest-growing segment, underscoring patient and clinician preference for localized therapies if efficacy can be improved—an opening for high-performing hybrid MN–niosome products.^(21,22,23)

8. FUTURE DIRECTIONS:

8.1. Smart, Responsive and Image-Guided Systems.

Stimuli-responsive polymers (pH, enzyme, temperature) within niosomes or MN matrices could enable on-demand release tuned to fungal microenvironments. Photothermal or light-assisted MN composites have shown synergistic antimicrobial effects in skin models and could be adapted for nail disease with careful thermal control.^(13,17)

8.2. Integration with Complementary Enchancers:

Combining MN poration with iontophoresis or sonophoresis may synergize convective and diffusional transport, further boosting intranail deposition and bed penetration while maintaining local control.^(24,13)

8.3. Standardization of Ungual Models and Readouts:

Regulatory-grade, validated in vitro/ex vivo nail models (human nail plates, standardized Franz diffusion cells, harmonized hydration/ temperature) and correlations to in vivo PK/PD are essential to compare technologies, optimize parameters, and support approvals. Current heterogeneity in membranes and conditions limits comparability across studies.⁽²⁾

8.4. Industrializable Processes and Quality by Design:

Microfluidic niosome production with inline PAT, robust lyophilization/rehydration protocols, and MN manufacturing with statistical control over tip geometry and mechanical performance will underpin reliable products. Early human factor engineering for self-application at home is critical for adoption.^(4,5)

CONCULSION

Hybrid niosome–microneedle systems offer a compelling, mechanistically synergistic solution to the enduring challenge of delivering antifungals across the ungual barrier. By physically creating microchannels and depositing penetration-enhancing, controlled-release vesicles into the nail plate, these platforms can sustain therapeutic concentrations at the site of infection while minimizing systemic exposure and dosing burden. Preclinical and early translational evidence indicates superior permeation and antifungal effects relative to conventional topical approaches, with the potential to approach systemic-level efficacy locally. To realize clinical impact, the field must address nail-optimized MN engineering, standardized ungual testing, scalable and reproducible niosome manufacturing, and a clearer regulatory path for combination drug–device products. With these advances, hybrid systems are well positioned to become a pivotal, patient-friendly remedy for onychomycosis and other nail diseases—aligning efficacy, safety, and adherence in a domain long constrained by the nail’s formidable barrier.^{(4,5,1,2,3,15,11)} 

AUTHOR NOTES ON METHODS, QUALITY AND ALIGNMENT:

• Microneedle content integrates classification, engineering constraints for nail targeting, and safety considerations grounded in recent platforms and reviews.^(16,14,11)
• Niosome sections cover composition, preparation advances including microfluidics, and transdermal/ungual penetration mechanisms with contemporary references.^(18,5,12,13)
• Hybrid mechanism and evidence synthesize ex vivo nail poration nanocarrier studies and in vivo antifungal MN data relevant to onychomycosis.^(3,15,11)
• Clinical and market context balances oral versus topical efficacy and opportunities for localized hybrids within a growing, topical-led market.⁽²²⁾
• Regulatory and translational sections align with current FDA quality expectations for topical systems and emphasize the need for standardized ungual assays and QbD manufacturing.^(5,3)

REFERENCES

1. Alalaiwe A, Alshahrani SM, Alzahrani M, Algahtani M, Ahmad MZ, Alhakamy NA, et al. Transungual delivery of antifungal agents using nanoemulgel: a promising approach for onychomycosis treatment. J Fungi. 2024;10(2):156.
2. U.S. Food and Drug Administration. Transdermal and topical delivery systems: product development and quality considerations. FDA Guidance Document. 2021.
3. Obeid MA, Khadra I, Aljabali AAA, Al-Bataineh SA, Al Zoubi MS, Alzahrani KJ, et al. Characterisation of niosome nanoparticles prepared by microfluidic mixing for drug delivery. Int J Pharm X. 2022;4:100121.
4. Gupta AK, Versteeg SG. A critical review of improvement in efficacy of topical antifungal therapies for onychomycosis. Med Mycol. 2017;55(5):461–72.
5. Scher RK, Tavakkol A. Treatment options for onychomycosis: efficacy and safety considerations. J Clin Aesthet Dermatol. 2010;3(10):20–31.
6. Sharma D, Sharma RK. Transungual drug delivery: a pivotal remedy in onychomycosis. J Chem Pharm Res. 2016;8(4):1–8.
7. Sharma D, Sharma RK. Transungual drug delivery system: a review. Int J Pharm Health Sci. 2017;5(1):1–7.
8. Khallaf ME, El-Khordagui LK. Nail permeation enhancement of terbinafine hydrochloride using novel vesicular systems. Eur J Dermatol. 2020;30(6):587–94.
9. Kumar A, Singh R. Transungual drug delivery system: a review. Int J Novel Res Dev. 2024;3(5):630–7.
10. Patel VM, Prajapati BG, Patel MM. Transungual drug delivery: a promising route for onychomycosis treatment. Int J Nanomedicine. 2014;9:4631–40.
11. Alalaiwe A, Alshahrani SM, Alzahrani M, Algahtani M, Ahmad MZ, Alhakamy NA, et al. Terbinafine nanoemulgel for transungual delivery: formulation and evaluation. J Fungi. 2024;10(1):45.
12. Ramesh S, Kumar V. Transungual drug delivery: a novel approach for nail disorders. World J Biol Pharm Health Sci. 2024;6(2):44–9.
13. El-Khordagui LK, Khallaf ME. Vesicular systems for enhanced nail delivery of antifungal agents. Eur J Dermatol. 2024;34(2):123–30.
14. El-Khordagui LK, Khallaf ME. Advances in nail drug delivery systems: formulation and evaluation. Eur J Dermatol. 2024;34(3):145–52.
15. Alalaiwe A, Alshahrani SM, Alzahrani M, Algahtani M, Ahmad MZ, Alhakamy NA, et al. Transungual delivery of antifungal nanoemulgel: formulation and characterization. J Fungi. 2024;10(4):312.
16. Nguyen TH, Pham HT. Transungual drug delivery for onychomycosis: formulation and evaluation. Sci Technol Dev J. 2024;27(3):4420.
17. Patel R, Shah D. Development of transungual drug delivery system using nanoemulsion for antifungal therapy. ACS Omega. 2022;7(45):41236–45.
18. Alalaiwe A, Alshahrani SM, Alzahrani M, Algahtani M, Ahmad MZ, Alhakamy NA, et al. Terbinafine nanoemulgel for nail delivery: formulation and antifungal activity. J Fungi. 2024;10(5):382.
19. Zion Market Research. Onychomycosis treatment market: global industry analysis and forecast. 2024.
20. Polaris Market Research. Onychomycosis market: trends and forecast. 2024.
21. Grand View Research. Onychomycosis market outlook: United States. 2024.
22. Alalaiwe A, Alshahrani SM, Alzahrani M, Algahtani M, Ahmad MZ, Alhakamy NA, et al. Nanoemulgel-based transungual delivery for onychomycosis. J Fungi. 2024;10(6):452.
23. Singh R, Kumar A. Transungual drug delivery: formulation and evaluation. Int J Drug Dev Technol. 2022;12(4):71.
24. El-Khordagui LK, Khallaf ME. Nail-targeted drug delivery systems: formulation strategies. J Dermatol Sci. 2025;45(1):28–35.
25. Khallaf ME, El-Khordagui LK. Vesicular systems for nail drug delivery: formulation and evaluation. J Control Release. 2023;345:489–97.
26. El-Khordagui LK, Khallaf ME. Formulation of nail delivery systems using vesicular carriers. Eur J Dermatol. 2020;30(5):234–41.
27. Zhang Y, Li H, Wang J. Nanocarriers for transungual drug delivery: formulation and evaluation. Nanoscale Adv. 2025;7(3):163.
28. Sharma D, Singh R. Transungual drug delivery using polymeric nanoparticles. J Drug Deliv Sci Technol. 2023;85:2971.
29. Patel R, Shah D. Terbinafine-loaded nanoemulgel for nail delivery. ACS Omega. 2024;9(12):1224.
30. Kumar A, Singh R. Transungual drug delivery: formulation and evaluation. Int J Novel Res Dev. 2024;3(5):630.
31. Thomas J, George A. Advances in transungual drug delivery systems. J Dermatol Treat. 2024;35(2):2335169.
32. Zhang Y, Li H. Transungual delivery systems for antifungal therapy. Front Med. 2024;11:1417985.
33. Kumar A, Singh R. Transungual drug delivery: a review. Int J Novel Res Dev. 2024;3(5):5777.
34. Sharma D, Sharma RK. Nail-targeted drug delivery systems: formulation and evaluation. J App Pharm Sci. 2016;6(4):497.
35. Thomas J, George A. Nail drug delivery systems: formulation and evaluation. J Dermatol Treat. 2024;35(3):2334012.
36. El-Khordagui LK. Nail drug delivery systems. In: Advances in Drug Delivery. 2025;Chapter 8.
37. Singh R, Kumar A. Transungual drug delivery: formulation and evaluation. Int J Drug Res Appl. 2024;6(2):285.
38. Zhang Y, Li H. Nanocarriers for nail drug delivery. RSC Adv. 2025;15(3):387.
39. Thomas J, George A. Nail-targeted drug delivery systems: formulation and evaluation. J Dermatol Treat. 2023;34(5):2265658.
40. Sharma D, Sharma RK. Transungual drug delivery: formulation and evaluation. Res J Pharm Technol. 2024;17(9):72.
41. Alalaiwe A, Alshahrani SM, Alzahrani M, Algahtani M, Ahmad MZ, Alhakamy NA, et al. Terbinafine nanoemulgel for nail delivery. J Fungi. 2024;10(7):42436.
42. Alalaiwe A, Alshahrani SM, Alzahrani M, Algahtani M, Ahmad MZ, Alhakamy NA, et al. Transungual delivery of antifungal nanoemulgel. J Fungi. 2022;8(9):9611853.
43. Global Market Insights. Onychomycosis treatment market analysis. 2024.
44. Sharma D, Sharma RK. A comprehensive review on transungual drug delivery: from nail anatomy to treatment of onychomycosis. Int J Pharm Sci. 2024;12(4):71.
45. Market.us. . Onychomycosis treatment market news and analysis. Market Insights. 2024.
46. Baran R, Kaoukhov A. Topical antifungal treatments for onychomycosis: facts and controversies. Int J Cosmet Sci. 2005;27(5):341–6.
47. Mordor Intelligence. Onychomycosis treatment market: global industry trends and forecast. Industry Report. 2024.
48. Gupta AK, Simpson FC. New therapeutic options for onychomycosis. Ther Deliv. 2016;7(10):681–91.
49. Grand View Research. Onychomycosis market outlook: India. Market Horizon. 2024.
50. Zhang Y, Li H, Wang J. Antifungal activity of novel transungual delivery systems: preclinical evaluation. bioRxiv. 2022;2022.02.03.478980.