Nanostructured Lipid Carrier-Based Nanoformulations for Atopic Dermatitis: A Comprehensive Review

Pratik Singh¹

¹Sun Pharma R&D Vadodara Gujarat, India.

¹Rungta College of pharmaceutical science and research, Bhilai.

Abstract:
Atopic dermatitis (AD) is a chronic inflammatory skin disease marked by barrier dysfunction, immune dysregulation, and pruritus. Conventional therapies often show limited efficacy due to poor skin penetration, side effects, and low adherence. Nanostructured lipid carriers (NLCs) offer a promising topical drug delivery platform to enhance skin targeting, controlled release, and patient compliance. This review highlights NLC design, formulation strategies, dermal penetration mechanisms, and immunomodulatory potential, with preclinical and emerging clinical evidence for corticosteroid-, immunosuppressant-, and phytochemical-loaded systems. Safety, regulatory considerations, and translational challenges are discussed, emphasizing the need for stimuli-responsive and personalized NLC approaches for effective AD management.

Keywords: Atopic Dermatitis, Nanostructured Lipid Carriers, Topical Drug Delivery, Skin Barrier Dysfunction, Controlled Release, Nanoformulations

1. INTRODUCTION

1.1. Epidemiological Burden and Socioeconomic Impact

Atopic dermatitis (AD) is a chronic inflammatory skin disease affecting over 230 million people worldwide, often starting in infancy and persisting into adulthood in severe cases. Prevalence is 20–25 % in children and 2–10 % in adults in developed countries. AD imposes a heavy socioeconomic burden, with high direct and indirect costs and a profound impact on quality of life due to itching, sleep loss, and psychological distress. (1,2).

1.2. Current Therapeutic Landscape and Clinical Shortcomings

First-line treatments for atopic dermatitis (AD), such as topical corticosteroids (TCS) and calcineurin inhibitors (TCIs), effectively reduce inflammation but pose risks with long-term use including skin atrophy, striae, and barrier disruption which, along with corticosteroid phobia (especially in children), hampers adherence. Severe or resistant cases may require systemic immunosuppressants (e.g., cyclosporine A, methotrexate, azathioprine), though their nonspecific action and toxicity (nephrotoxicity, hepatotoxicity, marrow suppression) restrict prolonged use (3). Biologics like dupilumab (targeting IL-4/IL-13) offer targeted immunomodulation and improved safety but are costly, injectable, and linked to side effects such as conjunctivitis and eosinophilia. Current therapies often fail to address epidermal barrier dysfunction or microbiome imbalance, and many topicals suffer from poor penetration, rapid clearance, and inadequate skin retention. These limitations highlight the need for advanced delivery systems that enhance percutaneous absorption, prolong local drug action, and minimize systemic exposure (4).

1.3. Advances in Nanotechnology for Dermatological Applications

Nanostructured lipid carriers (NLCs) are advanced delivery systems designed to overcome skin barriers in atopic dermatitis (AD). Comprised of solid and liquid lipids, their drug-accommodating crystalline core improves delivery over solid lipid nanoparticles. With a size under 200 nm, high surface area, and negative charge, NLCs enhance skin interaction, intercellular and follicular penetration. They offer sustained release, improved dermal retention, and support barrier repair by mimicking ceramides (5). Preclinical studies show that encapsulating corticosteroids, calcineurin inhibitors, herbal actives (e.g., curcumin, quercetin), and biologics in NLCs boosts anti-inflammatory efficacy and skin residence while reducing systemic toxicity. This review discusses AD pathophysiology, NLC design, lipid composition, size, charge, and fabrication methods, along with efficacy data and translational aspects including clinical trials, safety, and regulation. Future directions include stimuli-responsive, hybrid, and personalized NLC formulations, highlighting their promise in chronic dermatologic therapy(6).

 Atopic dermatitis (AD) (Figure 1) is a chronic inflammatory skin disorder characterized by intense itching, erythema, and skin barrier dysfunction. Its pathophysiology (Table 1) involves genetic predisposition (e.g., filaggrin mutations), immune dysregulation (Th2-mediated inflammation with IL-4, IL-13, and IL-31), and environmental triggers. Disrupted skin barrier function increases susceptibility to allergens and microbes, exacerbating inflammation. Therapeutic challenges include disease heterogeneity, limited long-term control, and side effects of prolonged steroid/immunosuppressant use. Emerging biologics (e.g., dupilumab) and JAK inhibitors offer targeted therapy, but personalized approaches and safer long-term treatments remain unmet needs.

2.1 Cutaneous Barrier Dysfunction and Immunopathogenesis

Atopic dermatitis (AD) is a chronic, relapsing skin condition characterized by barrier dysfunction, immune dysregulation, and itching. Genetic and environmental factors, particularly mutations in the filaggrin (FLG) gene, lead to a compromised epidermal barrier (7). These mutations reduce natural moisturizing factors, disrupt lipids, and increase water loss, allowing allergens, irritants, and microbes to penetrate. This breach triggers epithelial alarmins (TSLP, IL-33, IL-25), which activate dendritic cells and ILC2s, promoting a Th2 immune response. Th2 cytokines (IL-4, IL-5, IL-13) enhance IgE production, eosinophil infiltration, and further barrier disruption. Chronic AD evolves to involve Th1/Th22 responses, where IL-22 and IFN-γ cause skin thickening and sustained inflammation, maintaining barrier dysfunction (8).

2.2 Cytokine Networks and Microbiota Dysbiosis

The immunopathogenesis of AD shifts from an acute Th2/ILC2-driven phase to a chronic Th1/Th17/Th22 response, affecting immune activation, barrier function, neural sensitization, and microbial susceptibility. IL-4 and IL-13 inhibit antimicrobial peptides (β-defensins, cathelicidins), promoting Staphylococcus aureus colonization in over 90% of flares (9). The bacteria's exotoxins, proteases, and superantigens activate T cells and disrupt the epidermis. Dysbiosis, characterized by S. aureus overgrowth and loss of protective commensals (S. epidermidis, C. acnes), is a key feature of AD. S. aureus biofilms evade host defences and treatments, driving chronic disease. Transcriptomic and metagenomic data link reduced microbial diversity with severity, suggesting that restoring microbial balance may offer therapeutic potential (10).

2.3 Limitations in Drug Delivery to Diseased Skin

Delivering drugs to atopic skin is challenging despite its impaired barrier. Although increased permeability can aid passive diffusion, inflammation brings enzymatic degradation, altered pH, and elevated trans epidermal water loss, all reducing bioavailability and residence time(11). In acute lesions, edema and vesiculation dilute topical agents; in chronic lichenified skin, hyperkeratosis and fibrosis block penetration. Loss of ceramides disrupts lipid solubilization of lipophilic drugs, and upregulated esterases and proteases degrade many actives before they reach therapeutic levels. Moreover, systemic uptake especially in children raises risks of adrenal suppression and immunosuppression. Thus, formulations must boost local permeation and retention while ensuring safety (12).

2.4 Clinical Gaps and Need for Advanced Topical Systems

First-line therapies for atopic dermatitis, including topical corticosteroids and calcineurin inhibitors, alleviate symptoms but often cause skin atrophy, burning, tachyphylaxis, and poor retention, impacting adherence. Few delivery systems simultaneously restore the skin barrier and enable effective drug targeting (13). Nanostructured lipid carriers (NLCs) address these limitations by offering high drug loading, sustained release, and occlusion to aid barrier repair. They traverse the stratum corneum via intercellular, follicular, and transcellular routes, overcoming anatomical and physiological barriers of AD.  Moreover, lipid-based carriers may exert anti-inflammatory and reparative effects, enhancing therapeutic efficacy(14,15).

Table 1 Pathophysiological Factors and Drug Delivery Implications in AD (16,17)

3. SCIENTIFIC FOUNDATIONS OF NANOSTRUCTURED LIPID CARRIERS (NLCs)

Nanostructured Lipid Carriers (NLCs) have emerged as a promising nanocarrier system for drug delivery due to their unique structural and physicochemical properties. Their ability to deliver both lipophilic and hydrophilic drugs with enhanced stability and controlled release has garnered significant attention in pharmaceutical and dermatological applications (24).

3.1. Evolution from Solid Lipid Nanoparticles (SLNs) to NLCs: Design Rationale

Nanostructured lipid carriers (NLCs) address the limitations of solid lipid nanoparticles (SLNs), such as low drug loading and payload expulsion during storage. While SLNs provide biocompatibility and drug protection via solid lipid cores, their crystalline structure limits efficiency. NLCs combine solid and liquid lipids into a partially amorphous matrix, improving drug loading, encapsulation, and stability. The liquid lipid component enhances solubilization and enables controlled release of both lipophilic and hydrophilic APIs. Maintaining SLNs’ low toxicity and biocompatibility, NLCs offer superior therapeutic performance, making them ideal for topical and transdermal delivery, especially in chronic skin conditions like atopic dermatitis, where sustained retention and permeability are crucial (25).

3.2. Physicochemical Composition and Surfactant Selection

Nanostructured lipid carriers (NLCs) consist (Table 2) of solid lipids (e.g., glyceryl behenate, stearic acid) and liquid lipids (e.g., oleic acid, isopropyl myristate), stabilized by surfactants such as polysorbates, poloxamers, and lecithins. The typical solid-to-liquid lipid ratio (70:30–90:10) shapes NLC morphology, drug loading, and release behavior: solid lipids provide structure and sustained release, while liquid lipids reduce crystallinity and enhance drug solubilization. Optimal API-lipid compatibility is vital for high entrapment efficiency and prolonged delivery. Surfactants (1–5% w/w) lower interfacial tension, improving particle stability, size, zeta potential, and skin permeability (26). Non-ionic surfactants like Tween 80, Poloxamer 188, and Pluronic F68 are favoured in dermatology for low irritancy, especially on compromised skin. Their hydrophilic-lipophilic balance (HLB) further influences colloidal stability and release kinetics. Techniques such as DSC and XRD assess lipid melting and crystallinity, which correlate with drug entrapment and skin delivery performance. Solid lipids form the rigid NLC matrix, enabling controlled drug release and providing occlusive effects that support skin hydration and barrier repair. Liquid lipids disrupt crystal order, enhancing drug loading and reducing expulsion, while influencing viscosity and spread ability. Surfactants, particularly non-ionic types, stabilize the formulation by preventing aggregation and modulating key properties such as particle size, zeta potential, and interaction with skin. Balancing lipid ratios and surfactant HLB is essential for achieving high drug loading, colloidal stability, and controlled release (27,28).

Table 2: Classification of Lipid and Surfactant Components Used in NLC Formulations (29,30)

3.3. Types of NLCs: Structural and Functional Implications

Type I (imperfect crystal NLCs) combine solid lipids with small amounts of oil. The oil disrupts the solid-lipid crystal (normally triclinic β), creating imperfect polymorphs (orthorhombic β′ or amorphous α) with extra voids to host drug molecules. Over time, these less‑stable forms tend to convert (α → β′ → β), which can expel drug, so maintaining imperfections is key to retention (31).

Type II (multiple oil/fat/water NLCs) exploit the higher solubility of drug in liquid lipids. A hot Nano‑emulsion of oil and drug is cooled, and the resulting miscibility gap drives phase separation into oil Nano‑compartments within a solid lipid matrix. This structure greatly enhances loading capacity, since most API resides in the liquid‑lipid domains.

Type III (amorphous NLCs) are formulated to prevent lipid crystallization altogether. The matrix solidifies into an amorphous state, eliminating polymorphic transitions and thus preventing drug expulsion (32).

Although NLCs excel at delivering lipophilic drugs, hydrophilic peptides or proteins can also be loaded by forming lipid–drug conjugates (via salt or covalent linkages). These conjugates, processed as melts, yield nanoparticles with drug loadings up to 30–50%.

3.4. Comparative Advantages Over Conventional Nanocarriers

Nanostructured lipid carriers (NLCs) combine biocompatible, GRAS‑approved lipids with superior physicochemical stability and dermatological benefits. Unlike liposomes, which suffer low drug loading and phospholipid oxidation, and polymeric nanoparticles, which may require potentially toxic synthetic excipients, NLCs deliver both hydrophilic and lipophilic agents while controlling release kinetics and boosting drug retention in the stratum corneum. Their semi‑solid, gel‑like dispersions enhance topical ease‑of use and patient compliance, and their occlusive lipid matrix improves skin hydration and barrier restoration critical objectives in atopic dermatitis and other chronic inflammatory skin disorders (33)(34,35).

Table 3 Comparative Features of SLNs and NLCs (36)

4. NLCs MANUFACTURING AND FORMULATION STRATEGIES

4.1 High-Pressure Homogenization: Hot Vs. Cold Techniques

High-pressure homogenization (HPH) produces nanostructured lipid carriers (NLC) by passing a coarse emulsion through a narrow gap at 500–1,500 bar, where shear, turbulence, and cavitation reduce droplet size to the nanoscale. Cooling solidifies the lipid into NLC. Two main techniques are used:

Hot Homogenization

Lipids (e.g., glyceryl behenate, stearic/palmitic acids) are melted above their melting point, blended with liquid oil and drug, and emulsified in a hot surfactant solution. Homogenization occurs (3–5 passes at 500–1,500 bar), followed by cooling to recrystallize the nanoparticles. This method offers easy emulsification and small particles but risks degradation of APIs and surfactants due to heat (37).

Cold Homogenization

The lipid–drug melt is rapidly solidified (using liquid nitrogen or dry ice) and milled into microparticles, then dispersed in cold surfactant and homogenized at ambient temperature (5–10 passes at ~1,500 bar). This protects thermolabile actives and allows higher drug loading but introduces an extra milling step and broader particle size distribution. Both techniques are used to encapsulate anti-inflammatory agents (e.g., corticosteroids, calcineurin inhibitors, ceramides) for atopic dermatitis, leveraging the occlusive properties of NLC to enhance skin hydration and drug delivery to the stratum corneum (38). Formulation factors include lipid matrix composition (solid lipid and liquid oil, such as MCT or oleic acid) to create drug voids, and surfactants (e.g., Poloxamer 188, Tween 80, lecithin) chosen for their skin compatibility and thermal stability. Adjusting pH and ionic strength (e.g., NaCl, phosphates) controls zeta potential. Process parameters like pressure and cycle count affect particle size, energy input, and temperature. HPH is scalable, reproducible, and GMP-compliant. Hot HPH may lead to API degradation or lipid polymorphic shifts, while cold HPH prevents heat damage but risks aggregation if microparticles are too large. A hybrid approach, involving melting lipids and drug, cooling slightly above room temperature, milling, and homogenizing, balances these trade-offs (39,40)(41).

4.2 Emulsification-Solvent Evaporation and Alternative Methods

Emulsification–solvent evaporation is a low-energy, non-thermal technique for producing 30–200 nm nanostructured lipid carriers (NLCs). A drug-lipid mixture dissolved in a volatile solvent (e.g., ethyl acetate) is emulsified into an aqueous surfactant solution via high shear or sonication. Solvent removal (e.g., rotary evaporation) precipitates lipids into solid nanoparticles, preserving thermolabile actives and enabling precise lipid ratios, though solvent removal, scale-up, and regulatory compliance pose challenges (42). A variant, emulsification–diffusion, uses water-saturated solvents (e.g., acetone, ethanol) and water dilution to induce nanoprecipitation, often yielding smaller particles. Microemulsion methods rely on phase inversion of a lipid/co-surfactant/water system into cold water, producing fine NLCs but requiring strict compositional and thermal control. Top-down methods—ultrasonication, high-shear homogenization, membrane emulsification—are solvent-free but may result in broader particle sizes, contamination risk, or lower throughput. Supercritical CO₂ (PGSS) offers a green, solvent-free alternative, though it needs specialized equipment. Across all approaches, drug loading and stability depend on lipid composition (solid:liquid ratio), surfactant type/concentration (HLB 0.5–5%), co-solvents, ionic strength, and pH. For topical delivery, components must be non-irritant and skin-friendly (e.g., phospholipids, ceramide-like lipids)(43) (44).

4.3 Microfluidics and Emerging Technologies

Microfluidic systems offer a bottom-up method for producing uniform lipid nanoparticles by directing lipid and aqueous phases through precisely engineered microchannels, where mixing occurs via diffusion or induced perturbations. Common designs include T-junctions (shear-based droplet formation), hydrodynamic flow focusing (emulsion pinching), bifurcating mixers (stream splitting/recombination), staggered herringbone micromixers (chaotic advection via micro-ridges), and baffle mixers. Continuous operation enables millisecond-scale mixing with fine control over particle size (20–100 nm) and PDI through flow rate adjustments, requiring minimal energy. Inline PAT integration allows real-time monitoring, supporting continuous, modular pharmaceutical manufacturing. Microfluidic NLCs promote batch uniformity and gentle encapsulation of biomolecules, useful in atopic dermatitis therapy. Limitations like low throughput and clogging are being addressed via chip parallelization, robust reactors, and 3D-printed systems. Emerging technologies—acoustofluidics, electrohydrodynamic atomization, and droplet-based microfluidics—enable programmable, picoliter-scale mixing (45,46) .

4.4 Quality-By-Design (Qbd) And Process Optimization Approaches

A Quality-by-Design (QbD) framework is essential for robust NLC manufacturing in chronic dermatologic treatments like atopic dermatitis (AD). It starts by defining the Quality Target Product Profile (QTPP), covering dosage form, release kinetics, particle size, stability, and efficacy. Critical Quality Attributes (CQAs) such as particle size, zeta potential, drug loading, and stability are identified from the QTPP. Key Material Attributes (CMAs) like lipid composition and surfactant concentration, and Critical Process Parameters (CPPs) such as homogenization pressure, temperature, and mixing speed are evaluated using risk tools like Ishikawa diagrams and FMEA (47,48). For instance, fishbone analysis may link lipid polymorphism or cooling rates to particle uniformity. Design of Experiments (DoE) systematically tests the impact of CMAs and CPPs on CQAs, revealing interactions like how increased oil may enhance drug loading but enlarge particles. This helps define a design space with parameters like pressure/temperature conditions to achieve desired particle size and entrapment. Process Analytical Technology (PAT) tools, such as DLS, NIR spectroscopy, and turbidity meters, enable real-time monitoring. Ultimately, QbD ensures consistent drug release and minimizes irritants, addressing variability and ensuring product robustness for AD therapies (49,50).

Comprehensive physicochemical characterization (Figure 3) is vital to ensure nanostructured lipid carriers (NLCs) for atopic dermatitis (AD) deliver drugs safely and effectively. Advanced analytical techniques provide detailed insights into NLC structure, composition, and behavior, which are key to their performance. Critical parameters such as particle size, morphology, drug loading, lipid crystallinity, and rheology must be quantified and optimized, as they affect interaction with the stratum corneum, drug release, and formulation stability. The following subsections review key methods for measuring these attributes and their relevance to delivering corticosteroids, calcineurin inhibitors, and other anti-inflammatory agents via NLCs for AD(51) .

5.1. Particle Size, Distribution, and Surface Charge

The mean particle size and distribution of NLCs are key indicators of skin penetration potential and physical stability. Dynamic light scattering (DLS) is the primary sizing method, providing Z-average diameter and polydispersity index (PDI). NLCs generally range from 50–300 nm, with a narrow size distribution (PDI ≤ 0.2–0.3) preferred to ensure uniform drug delivery and minimize aggregation. While DLS is suitable for submicron particles, complementary methods like laser diffraction (LD) and field-flow fractionation (FFF) help analyze broader size ranges and complex populations (52). LD captures larger or agglomerated particles, whereas FFF enables detailed fractionation. Microscopy (TEM, AFM) offers number-based size data but is less efficient. Particle size strongly influences topical delivery: smaller NLCs increase surface area, enhance occlusion, and improve drug diffusion. Sub-200 nm NLCs show superior hydration and uptake, and those <100 nm may reach hair follicles (53,54). For AD therapy, particles are kept below ~300 nm to avoid systemic absorption. Size is tuned via process (e.g., homogenization, sonication) and formulation parameters (lipid/surfactant content). Higher surfactant or mixed lipids reduce size and PDI by stabilizing emulsions. Surface charge, measured by zeta potential, is also vital: values above ±30 mV ensure electrostatic repulsion and colloidal stability. NLCs typically exhibit negative zeta (–20 to –40 mV), though cationic agents like chitosan or CTAB yield positive values. Charge affects skin interaction—cationic NLCs enhance adhesion and drug accumulation, while neutral or mildly negative ones reduce irritation. Thus, reporting both size and zeta potential is essential for optimizing NLC performance (55).

5.2. Morphological and Topographical Studies (TEM, SEM, AFM)

Microscopic methods enrich dynamic light scattering by revealing NLC shape, surface detail and internal architecture. Transmission electron microscopy (TEM) the benchmark resolves individual lipid particles (often spherical or quasi‑spherical), with negative staining (e.g. uranyl acetate) highlighting edges and cryo‑TEM preserving hydration. TEM can expose core shell or multi‑compartment structures, though drying, staining or freezing may induce aggregation or deformation (56). Scanning electron microscopy (SEM) complements TEM by showing surface topography and roughness after metal coating and vacuum dehydration but cannot probe internal features and may introduce artifacts from surfactant removal. Atomic force microscopy (AFM) maps 3D surface profiles and measures particle height and diameter without staining, yet soft NLCs can flatten during drying. Cross‑validation among TEM, SEM and AFM distinguish genuine morphology from preparation artifacts. In dermal or transdermal formulations, uniformly spherical NLCs (as seen by TEM and AFM) ensure consistent drug loading and release; irregular or crystalline particles are redispersed or filtered out. AFM’s 3D spreading profiles further inform skin‑interaction studies. Together, these imaging techniques corroborate DLS size distributions and confirm absence of larger contaminants that could impair drug delivery (57).

5.3. Drug Encapsulation Efficiency and Release Profiles

Encapsulation efficiency (EE) and drug loading (LC) indicate the amount of drug in NLCs for AD therapy. High EE and disordered lipid matrices enable sustained, localized release of lipophilic drugs like tacrolimus, prolonging effect and reducing dosing, typically showing biphasic release in vitro with minimal systemic absorption (58)(59).

5.4. Thermal, Crystallinity, and Spectroscopic Analysis

Thermal and structural analyses (DSC, XRD, FTIR, Raman) reveal NLC lipid organization, drug state, and molecular interactions. Reduced crystallinity, amorphous drug dispersion, and polymorphic transitions indicate stable, well-incorporated drug matrices(60).

5.5. Rheological Behavior and Stability Assessment

NLC rheology and stability ensure topical efficacy: shear-thinning, moderate-viscosity gels improve spreadability, skin retention, and occlusion, while stability tests (physical, chemical, microbiological) confirm uniform, long-lasting formulations for AD therapy (63,64).

Figure 4 Skin‐penetration pathways of lipid nanoparticles (LNPs)

6. MECHANISTIC INSIGHTS INTO SKIN DELIVERY VIA NANOSTRUCTURED LIPID CARRIERS (NLCs)

6.1. Penetration Pathways: Stratum Corneum to Dermis

NLCs cross the stratum corneum via intercellular, transcellular, and trans-appendageal (follicular) routes. Their small size, positive charge, and lipophilicity enhance SC adhesion and penetration, allowing dual drug delivery through lipid fusion and surfactant-mediated disruption for deeper skin targeting(66).

Table 4 Lipid Matrix Interactions (67,68)

NLCs form an ultrathin, occlusive lipid film on skin, reducing water loss, hydrating the SC, and fluidizing lipid layers to enhance drug penetration. Small (~200 nm), solid-lipid-rich NLCs with skin-compatible lipids and surfactants maximize occlusion, SC elasticity, and epidermal delivery.(69,70).

6.3. Immunomodulatory and Anti-inflammatory Mechanisms

In AD, NLCs improve delivery of corticosteroids and calcineurin inhibitors, sustaining epidermal drug levels, reducing systemic exposure, and better suppressing inflammation. Follicular targeting and uptake by immune cells enhance efficacy, minimize side effects, and accelerate lesion resolution compared to conventional creams (71).72,73)

6.4. Sustained Drug Release and Epidermal Retention

NLCs, combining solid and liquid lipids, provide burst-plus-sustained drug release and follicular reservoirs, enhancing epidermal delivery and prolonging therapeutic levels. Release is modulated by lipid crystallinity, solid–liquid ratio, particle size, and bioadhesive excipients (74,75). NLCs act as controlled-release depots, extending local therapy, reducing systemic exposure, and maintaining steady drug levels via follicular and intercellular reservoirs. Lipid composition and surfactants optimize skin retention and therapeutic outcomes

Table 5 Key formulation factors(76,77)

 7. NLCs BASED FORMULATIONS FOR ATOPIC DERMATITIS

Topical corticosteroids (e.g., hydrocortisone, betamethasone) effectively control atopic Steroid-loaded NLCs enhance drug loading, controlled release, skin penetration, and occlusion, improving epidermal retention, anti-inflammatory activity, and hydration while reducing systemic exposure. Emerging NLCs with immunomodulators or penetration enhancers further boost efficacy and safety compared to conventional creams. (79).

   Table 6 Summary of corticosteroid-loaded NLCs evaluated in preclinical models (80,81).

7.2. Immunosuppressants and Biologics via NLCs

NLCs enhance topical delivery of calcineurin inhibitors, cyclosporine, and other immunomodulators by improving solubility, controlled release, and follicular/epidermal targeting, reducing systemic exposure. They enable co-delivery of synergistic agents, including siRNA, though challenges remain in stability, high-load formulation, and long-term safety for large molecules(84,85).

       Table 7 NLC-based formulations for immunosuppressants in AD therapy (86,87).

7.3. Herbal and Natural Actives in NLC Systems

Plant-derived anti-inflammatory and antioxidant actives (polyphenols, flavonoids, carotenoids, essential oils) face solubility, stability, and photodegradation issues in AD. NLCs enhance solubilization, protection, sustained release, and skin deposition, with co-encapsulation strategies further boosting bioavailability; some, like Thykamine, are now in clinical trials (91)(92).          

Advantages: NLCs protect unstable botanicals, mask undesirable odours/tastes, and enhance skin penetration by mimicking lipids. They also prolong the local exposure of actives, preventing rapid wash-off.

Challenges: Variability in natural extract composition can affect NLC structure. Oils may alter crystal formation, and plant compounds pose a risk of skin sensitization. Achieving therapeutic concentrations from diluted actives is challenging, and regulatory classification (cosmetic vs. drug) adds complexity for "herbal NLC" products (93,94).

7.4. Comparative Studies: In Vitro, Ex Vivo, and Animal Models

Nanostructured lipid carriers (NLCs) consistently surpass conventional topical formulations in sustained release, skin permeation, efficacy, and safety. (Table 9) In vitro studies show non-Fickian kinetics—e.g., clobetasol propionate NLCs follow Higuchi kinetics, sustaining release over 24 hours versus rapid release from plain gels. Ex vivo assays reveal 2.5–2.6 times greater deposition and flux of mometasone furoate or betamethasone from NLC hydrogels than from marketed creams, due to their lipid makeup and nanoscale size enhancing stratum corneum penetration (95). In atopic dermatitis models, NLC gels (e.g., clobetasol, cyclosporine) reduce edema and ear thickness faster and more durably than standard gels, with histology confirming less hyperplasia and infiltration and minimal irritation. While no model fully mimics human pathology and scale-up demands reproducibility, converging in vitro, ex vivo, and in vivo data support NLCs as superior vehicles for topical drug delivery and therapeutic efficacy (96,97).

Table 9 comparative studies of NLC vs conventional formulations

7.5. Clinical Trials and Real-World Evidence

(Table 10) Most nanostructured lipid carrier (NLC) research for atopic dermatitis (AD) remains preclinical, and no NLC-based therapy has reached late‑phase trials or market approval. Current clinical studies target small molecules, biologics, and natural extracts, with none specifically evaluating NLC formulations though NLCs have shown good tolerability in other contexts (e.g. spironolactone‑NLC gel for acne). Lipid creams (e.g., ceramide emulsions) and nanoparticle‑enhanced cosmetics indirectly aid AD but aren’t classified as nanocarriers, and there is no systematic real‑world NLC data in AD. Translational hurdles include formulation complexity, regulatory requirements, and the need for rigorous safety testing and proof of clinical benefit over existing treatments. Preclinical data highlight NLC advantages, yet clinical evidence is lacking. Future work should prioritize early human trials, safety and efficacy monitoring, and real‑world observational studies. Insights from other nanomedicines indicate NLCs could ultimately enable targeted delivery, lower toxicity, and better adherence in AD management (98)(99).

Table 10 Examples of therapeutic agents formulated in NLCs for AD and their comparative outcomes in preclinical studies. (NLC = nanostructured lipid carrier.) Each study reports the improvement of the NLC system over a conventional formulation.

*Each column highlights the formulation and model used, and the improved outcome achieved by the NLC system, as quantified in the cited references. These comparative studies reinforce that NLC carriers can substantially enhance topical drug delivery and efficacy in AD models relative to standard formulations.

7.6 Benefits of Nanostructured Lipid Carriers in Skin Care and Topical Drug Delivery

Nanostructured Lipid Carriers (NLCs) improve on solid lipid nanoparticles by combining solid and liquid lipids into a less-ordered matrix that boosts drug loading, stability, and controlled release. This loose structure accommodates more hydrophilic and lipophilic actives, protects sensitive ingredients from degradation, and extends shelf life. Sustained release lowers application frequency, enhancing compliance and reducing systemic exposure (100,101). Their small, lipid-based particles penetrate deeper into skin, improving hydration, while biocompatible lipids ensure tolerance even on sensitive skin. NLCs can be tailored into creams, gels, sprays, or masks for customized dermatological therapies and high‑performance cosmetics (102)(103).

Table 11 NLC Formulations for Atopic Dermatitis(104,105) (106,107)

8. Dermatological Safety and Nano Safety Considerations

8.1 Skin Irritation, Sensitization, and Phototoxicity          

Nanostructured lipid carriers (NLCs) use biocompatible, GRAS lipids to provide controlled release and occlusion. Although their surfactants can potentially irritate or sensitize, standard dermal safety assays (OECD TG 439, TG 404 for irritation; TG 442D/E or LLNA TG 429 for sensitization) consistently show low irritation. For example, podophyllotoxin‑loaded NLCs caused no erythema or edema in rabbits, and radiolabelled NLCs applied to rat wounds showed no systemic uptake, cytotoxicity, sensitization, or irritation. NLC‑based gels also induce less redness than conventional gels, matching the excellent tolerability of solid lipid nanoparticles versus polymeric carriers. While NLCs themselves aren’t photoreactive, they can modify payload light exposure; in vitro phototoxicity tests (OECD TG 432, TG 498) are therefore recommended for UV‑activatable drugs. For instance, a methoxsalen ethosomal gel produced less UV‑induced erythema than a standard cream, suggesting lipid encapsulation can reduce phototoxicity but any NLC carrying photosensitizers still needs UV‑exposure testing (108)(109).

8.2 Systemic Exposure and Long-Term Safety

Topical NLCs form an occlusive film that enhances drug retention in the stratum corneum and epidermis while limiting systemic absorption. In rat studies, ^99mTc-labeled NLCs remained at the application site for 24 hours with no detectable systemic distribution. Dermatopharmacokinetic data show superior local drug retention with NLCs compared to standard formulations. In humans, tretinoin NLC gel achieved similar efficacy with reduced transepidermal water loss, indicating improved skin targeting and minimal systemic exposure (110). Unlike conventional emulsions or ethanol-based solutions, NLCs limit systemic spillover. (       Table 12) They are metabolized by skin and hepatic lipases into benign byproducts, reducing concerns of long-term accumulation. Animal studies report no histopathological changes or sensitization, even in compromised skin. Nevertheless, chronic exposure studies (e.g., subchronic toxicity, carcinogenicity) are advised for long-term use. Compared to synthetic polymeric nanoparticles, NLCs exhibit a safer profile due to their biodegradable lipid content, though safety should be assessed case-by-case using protocols like OECD TG 417 and genotoxicity assay (111) .

                 Table 12 . Toxicological endpoints and relevant test methods for dermal nanocarriers

8.3 Regulatory Guidelines for Nanomaterial Safety in Dermatology

Regulatory agencies are increasingly focused on the safety and efficacy of nano-enabled dermatological products. In the EU, Regulation (EC) 1223/2009 mandates premarket notification and a six-month review for cosmetics with nanomaterials, while the SCCS’s 2023 guidance requires detailed physicochemical characterization, exposure assessment, and tailored toxicology. For medicinal products, EMA reflection papers demand adherence to conventional safety standards with added justification for nano-specific features. Likewise, the FDA has issued guidance for cosmetics and, in 2022, draft guidance for drug products, emphasizing comprehensive nanoscale material characterization and quality control. (Table 13) Both agencies maintain core principles of safety, efficacy, and quality, while addressing nano-specific concerns such as particle persistence and altered immunogenicity (112). International bodies like OECD and ISO are working to harmonize nanotoxicology testing, focusing on endpoints like irritation, sensitization, and phototoxicity. A consensus supports case-by-case risk assessments incorporating nanoscale features and non-animal testing. Effective evaluation of NLC dermal formulations combines traditional toxicology with nanotoxicology, using preclinical models (e.g., human 3D skin, rodents), human data, and OECD/ISO-backed weight-of-evidence approaches (113)(114).

Table 13 Regulatory Guidelines for Nanomaterial Safety in Dermatology

9. TRANSLATIONAL AND COMMERCIAL OUTLOOK

9.1. Regulatory Pathways for NLC-Based Dermatologics

Nanostructured lipid carriers (NLCs) for topical therapeutics are regulated as drug products within existing pharmaceutical frameworks. In the U.S., they fall under FDA/CDER jurisdiction, evaluated on a case-by-case basis for composition and use, with no new regulatory category. The 2017 FDA draft guidance emphasizes nanotechnology-derived drug safety and efficacy, while the 2022 guidance for generic semisolid dermatologics recommends in vitro permeation tests (IVPT) for bioequivalence (115). The EMA applies standard medicinal product regulations to NLCs, offering general guidance, while in India, the CDSCO treats all nanopharmaceuticals as new drugs requiring full IND-level data. Regulatory bodies stress the Quality-by-Design (QbD) approach, focusing on attributes like particle size and composition, and recommend early consultations for nanospecific concerns. In summary, NLC-based topicals follow standard drug regulations with nanospecific guidelines shaping the review process (116).

9.2. Intellectual Property and Patent Trends

The patent (Table 14) landscape for nanostructured lipid carrier (NLC) drug delivery is rapidly expanding, covering compositions, manufacturing methods, and applications by universities, biotech firms, and industry leaders. For example, Florida A&M University holds US 8,715,736 B2 (2014) for peptide-coated NLCs enhancing transdermal delivery (117,118). In China, Suzhou Nanohealth Biotech patented a cosmetic NLC with phenylethyl resorcinol, while L’Oréal and Univ. Campinas filed WO 2017/185155 for NLCs with murumuru butter. Aché and Ferring's Brazilian patent (WO 2023/137532) covers NLCs with natural oils as UV filters. Though patent filings peaked in the 2010s, recent ones focus on specific applications, with broad claims on mixed-lipid systems alongside niche patents like EP 3474864 A1 (2020) targeting Helicobacter pylori. Patents mainly address lipid matrices, nanoparticle preparation, and targeted uses, with global assignees from universities, research institutes, and companies. Utility models and formulation patents continue to protect NLC technologies, reflecting ongoing R&D interest despite potential proprietary constraints (119).

Table 14 NLC-related patents

9.3. Marketed Formulations and Industrial Perspectives

While no FDA-approved NLC drug exists for atopic dermatitis (AD), NLCs have demonstrated success in dermatology, starting with cosmeceuticals like Cutanova® Nanorepair Q10 (2005) and Nanobase® cream, known for skin compatibility and hydration. Major cosmetics brands, including L’Oréal, incorporate NLCs in sunscreens and anti-aging products. NLCs like DPK-060 (an antimicrobial peptide for AD) enhanced stability and skin delivery, although Phase II trials were halted due to instability. Tacrolimus and cyclosporine also showed improved skin retention in NLCs, but none advanced to late-stage trials. The global dermatologic market, projected to grow from ~$95B in 2020 to ~$140B by 2026, remains largely dominated by low-cost generics, demanding clear NLC benefits. Investment trends are mixed, with IDRI licensing its NLC vaccine platform to Amyris, but high trial costs dampen enthusiasm. NLCs can be produced using scalable, eco-friendly methods, yet challenges like lipid crystallinity and sterilization persist. Despite these hurdles, strong patent activity and ongoing R&D highlight growing interest in NLCs for skin diseases(120).

9.4. Barriers to Clinical Translation

Translating NLC-based dermatologics to clinical use faces several challenges. Despite using biocompatible lipids and surfactants, long-term safety of nanoparticle application is under-researched, raising concerns about inflammation and microbiota changes. Surfactant choice impacts NLC toxicity and stability, necessitating extensive dermal toxicity testing(121). Achieving consistent stability, particle size, and lipid polymorphism is difficult, with high-shear homogenization often producing variable results. Scaling up (122)complicates production with heat transfer issues and storage-induced lipid transitions. (Table 15) Regulatory pathways are unclear, with NLCs possibly classified as new molecular entities or requiring bioequivalence evaluations, especially in markets like India. Commercially, NLCs must offer therapeutic benefits to justify costs, with factors like vehicle feel and cost-effectiveness influencing adoption. Patent limitations and large clinical trial requirements further hinder progress. Success depends on clear regulatory strategies, robust safety data, and strong academic–industry collaboration (123,124)

Table 15 Examples of NLC-based dermatologic products and candidates. (N/A = not available; preclinical/investigational status in parentheses)

Each example demonstrates either a marketed product (cosmetic) or a promising candidate. Continued progress will depend on resolving formulation issues at scale, and generating human data showing that NLCs confer meaningful clinical or cosmetic advantages over conventional therapies.

10. FUTURE OUTLOOK AND EMERGING INNOVATIONS

10.1. Stimuli-Responsive and Smart NLCs

Table 16 Conventional NLCs vs Stimuli Responsive NLCs

10.2 Personalized NLC-Based Therapeutics

AD’s heterogeneity supports personalized NLC therapies, with biomarker-driven payloads and lipid composition tailored to immune profile, genetics, or microbiome. AI-guided, theranostic, and “N-of-1” approaches may optimize efficacy and safety (130).

Figure 8 Illustration of NLCs Delivery to AD-Affected Skin

10.3 Hybrid Systems: Microneedles, Hydrogels, and Patches

Hybrid platforms combining NLCs with microneedles, hydrogels, or transdermal patches enhance AD therapy by improving dermal localization, sustained release, and skin hydration. While promising, challenges like uniform NLC dispersion and barrier penetration remain for
clinical translation. (131)

Table 17 compares these platforms and their attributes in the context of AD delivery

Figure 9 Bench-to-bedside Roadmap for NLCs Based Therapeutics

10.4 Translational Gaps and Research Roadmap

Translating NLCs into clinical therapies for AD faces challenges in preclinical modeling, manufacturing, regulation, and clinical evaluation. Advanced human-relevant models, standardized assays, robust GMP production, biomarker-driven patient stratification, and AI-guided dosing are needed to enable safe, effective, and personalized NLC-based treatments.

(133,134).

Table 18 NLC Formulations for Atopic Dermatitis

MARKETED PRODUCTS AND CHALLENGES IN THE TRANSLATION OF NLC-BASED DERMATOLOGICAL FORMULATIONS FOR ATOPIC DERMATITIS

Nanostructured lipid carriers (NLCs) offer improved drug loading, stability, and controlled release over solid lipid nanoparticles, with potential for AD therapy. Marketed lipid nanoparticle products demonstrate feasibility, but clinical translation faces challenges in scalable production, cost, patient adherence, regulatory approval, and long-term stability.

FUTURE OUTLOOK

NLCs show strong potential for delivering poorly soluble anti-inflammatory and natural agents in AD therapy. Successful translation requires scalable, cost-effective manufacturing, patient-centric design, and robust preclinical and clinical validation to enable safe, effective topical treatments.

SAFETY OF NANOCARRIER-BASED DERMO PHARMACEUTICAL FORMULATIONS FOR ATOPIC DERMATITIS: REGULATORY AND TOXICOLOGICAL ASPECTS

Nanocarriers (NCs) offer promising topical treatments for AD due to enhanced skin penetration and drug delivery, but their small size raises toxicity concerns, including systemic absorption and immune reactions. Studies on damaged skin, particle modifications, and surface coatings are needed to mitigate risks. Clear regulatory guidelines from bodies like the EMA and FDA are essential for safe clinical translation.

(135)(136,137).

CONCLUSION

AD is a complex inflammatory skin disorder with limited treatment options, especially in chronic cases where pharmacological therapies show suboptimal efficacy and adverse effects. Nanocarriers (NCs), including NEs, LIPs, SLNs, and NLCs, offer targeted, controlled drug delivery, improving skin retention, permeation, and therapeutic outcomes. While preclinical studies are promising, challenges remain in safety profiling, standardization, and clinical translation, highlighting the need for further research to enable marketable, nanotechnology-based AD therapies.