Nanotechnology based topical drug delivery systems for psoriasis addressing current strategies clinical progress and manufacturing challenges

Abstract

Psoriasis is a chronic, immune-mediated inflammatory disorder affecting more than 40 million individuals worldwide, with prevalence rising steadily over the past three decades. Conventional topical formulations, including creams and ointments, show limited clinical success due to poor drug penetration through the hyperkeratotic psoriatic stratum corneum, instability of actives, and suboptimal patient adherence. Although systemic and biologic agents offer higher therapeutic efficacy, their use is restricted by immunosuppression, cost, and long-term safety concerns. Nanotechnology-based topical delivery systems including lipid-based carriers, polymeric nanosystems, microneedles, nanoemulsions, nanosponges and nanofibers have emerged as promising alternatives capable of enhancing skin penetration, improving drug stability, enabling controlled release, and reducing systemic exposure. Several preclinical and clinical studies have reported improved Psoriasis Area and Severity Index reductions, enhanced drug retention, and superior tolerability with methotrexate, tacrolimus, and calcipotriol based nanoformulations. Despite these advancements, challenges remain related to manufacturing scale-up, quality-by-design implementation, batch reproducibility, regulatory evaluation, and economic feasibility. This review critically summarizes current nanotechnology-enabled approaches for topical management of psoriasis, compares their therapeutic performance, highlights translational limitations, and discusses future perspectives for clinical adoption and commercialization.

Introduction

Psoriasis is a long lasting skin condition caused by the immune system. It features rapid skin cell growth, abnormal activation of certain immune cells like dendritic cells, macrophages, and T-cells and ongoing overproduction of cytokines [1]. The disease arises from a mix of genetic factors, immune system problems, and environmental triggers such as trauma, infections, stress, and certain medications. Around the world psoriasis impacts over 40 million people. The prevalence has risen from 1.1% in 1990 to almost 1.4% in 2024. This increase reflects both better recognition of the disease and more environmental risk factors [2, 3].

Clinical burden and limitations of conventional therapy

Psoriasis appears as long lasting red and scaly patches. These are often itchy and can cause burning sensations which significantly affect a person's quality of life. Besides skin issues the disease is closely linked to metabolic syndrome, heart problems, and mental health issues like depression and social withdrawal [4, 5].

Conventional topical therapies such as corticosteroids, vitamin D analogues, coal tar, salicylic acid, and retinoids are still the first choice for treatment [6]. However, they often produce less than ideal results. One major issue is that many anti-psoriatic drugs including tacrolimus, cyclosporine, acitretin, calcipotriol, and methotrexate do not dissolve well in water. This limits their effectiveness in passing through the thickened hyperkeratotic stratum corneum [7, 8].

Traditional methods to improve solubility like surfactants, penetration enhancers, co-solvents (such as ethanol and propylene glycol), salt formation, pH adjustment, and complexation (like cyclodextrins), can boost solubility but they often lead to skin irritation, instability, drying precipitation, or inadequate permeation through psoriatic plaques [9]. These standard approaches struggle to keep therapeutic levels in the deeper layers of the skin or maintain stability in normal body conditions.

Additionally, many traditional topicals are greasy, hard to use, and require frequent application, which reduces adherence [10]. Systemic therapies and biologics while more effective, come with risks like liver damage, weakened immune response, and high costs, especially in low resource settings. Together, these issues point out the need for better, stable, and patient friendly topical delivery methods [11, 12].

Need for improved topical delivery

Achieving effective drug levels in the deeper layers of the skin while keeping systemic exposure low is a major challenge in treating psoriasis. Traditional methods to improve solubility, like surfactants, penetration enhancers, and co-solvents can increase drug availability [13–15]. However, they often cause irritation, instability, and inadequate penetration through thick psoriatic plaques. These challenges highlight the need for new topical systems that can improve penetration specifically target inflamed tissues, and offer controlled, long-lasting release [16, 17]. This review provides a structured assessment of how nanotechnology based systems can overcome these obstacles and enhance treatment results. this work presents several unique strengths: A critical, quantitative comparison of lipid-based, polymeric, and device-assisted nanosystems. To support this thorough evaluation the review is organized to guide the reader through the epidemiology of psoriasis, key drug delivery barriers, nanotechnology-based topical systems, emerging device-assisted strategies, clinical translation, manufacturing challenges, limitations, and future perspectives. This combined approach seeks to provide a better understanding of how modern nanocarrier platforms can address the drawbacks of traditional therapies and speed up the development of effective, patient focused topical treatments for psoriasis.

Psoriasis: global burden and unmet needs

Psoriasis affects more than 40 million people worldwide and continues to create significant clinical, psychological, and economic challenges. The global prevalence increased from about 1.1% in 1990 to nearly 1.4% in 2024 with higher rates found in high income areas. Despite this increase epidemiological data are still lacking in over 70% of countries. This gap leads to underreporting and delays in diagnosis particularly in low resource settings [18, 19].

Patients deal with chronic inflammation, itchy and painful plaques, social stigma, limited mobility, and sleep issues [20]. Other health problems including metabolic syndrome, obesity, diabetes, and a nearly 50% higher risk of long-term heart disease, make the situation even more complicated. Psychosocial distress is high almost 80% of patients quality of life suffers because of visible lesions and a long-lasting illness [21–23].

Economically psoriasis leads to higher healthcare costs, missed workdays, and lower productivity. Total costs reach almost USD 110 billion each year in the United States. In countries like India access to treatment is still limited, particularly for advanced biologics because of affordability issues [24, 25].

Topical agents work well for mild to moderate cases. However, issues like poor adherence, limited penetration, and local irritation lessen their effectiveness [26, 27]. Systemic therapies and biologics offer greater efficacy but come with concerns about immunosuppression, liver damage, and high treatment costs. These challenges highlight the need for better drug delivery methods that can boost local effectiveness while reducing systemic risks [28, 29].

Drug delivery challenges in psoriasis

Successful topical therapy needs enough medication to penetrate the deeper layers of the epidermis and dermis without triggering side effects throughout the body. However, various physiological and pathological barriers reduce the effectiveness of traditional formulations [28].

Stratum corneum barrier

The stratum corneum is the main barrier to delivering drugs to the skin. In psoriasis this layer thickens, becomes abnormal, and loses its structure. This condition makes it harder for water-soluble and poorly soluble drugs to penetrate. Traditional ointments and creams often do not penetrate enough to reach the overactive keratinocytes and immune cells [28, 29].

Altered lesional microenvironment

Psoriatic plaques have several changes that impact how topical drugs are delivered. They show increased blood vessel permeability and higher levels of inflammatory cytokines. The lipid content in the outer layer of the skin is also lower [30]. The skin surface has a slightly more acidic pH of about 4.4 while healthy skin has a pH of 4.9. Furthermore, oxidative stress is significantly higher in psoriatic lesions. These factors can speed up drug degradation, lower overall bioavailability, and prevent drugs from being evenly distributed in the affected area [16, 21].

Solubility and stability issues

Important anti-psoriatic molecules like methotrexate, tacrolimus, calcipotriol, acitretin, and several newer small molecule agents often encounter major formulation issues. These problems arise from their low water solubility, sensitivity to light or oxidation, and instability in standard topical bases. Common methods to improve solubility, such as adding surfactants, organic solvents, or penetration enhancers, often cause skin irritation and still do not effectively break through the thick and resistant psoriatic barrier [31, 32].

Lack of sustained and targeted delivery

Most topical agents need to be applied often because they are quickly removed from the skin surface have limited retention in the viable epidermis, and do not localize well in inflamed psoriatic tissues. Without controlled and sustained drug release, therapeutic results suffer and the risk of local irritation increases [31, 32].

Patient adherence

Topical treatments are often messy and greasy. They also need to be applied multiple times which can make people less adhere with them (Table 1).

Table 1.

Global psoriasis burden and economic impact [2, 18, 19]

Region/country	Prevalence (%)	Key findings	Economic burden
United States	~ 2.2	High CVD risk, significant Quality of life reduction	~ 110 billion USD/year
Europe (Average)	1.5–2.0	High comorbidity burden	~ 50 billion USD/year
India	0.4–0.5	Low biologic access, stigma contributes to poor Quality of life	~ 5.2 billion USD/year
China	0.6	Increasing prevalence with urbanization	Rising healthcare costs
Middle East	~ 1.2	High obesity linked risk	Moderate healthcare burden
Africa	~ 0.5	Underreported prevalence	Low due to limited reporting
South America	0.6–1.0	Growing prevalence	Moderate burden
Global Average	~ 1.4	Strong association with systemic inflammation	Not reported

Classification of novel nanotechnology systems for topical psoriasis therapy

Nanotechnology based drug delivery platforms address the limitations of traditional topical treatments. They improve solubility, penetration, retention, and targeted release. These systems are divided into three main classes: lipid-based nanocarriers, polymeric nanosystems, and hybrid and emerging nanotechnologies. Each class features various systems with unique structural and functional traits. Case studies illustrate significant advancements in this field.

Lipid based nanocarriers

Lipid nanocarriers mimic the lipid-rich stratum corneum. They improve penetration and drug deposition. Major systems include liposomes, ethosomes, niosomes, solid lipid nanoparticles (SLN), and nanostructured lipid carriers (NLC).

Liposomes

Liposomes are small, spherical vesicles composed of phospholipid bilayers that can encapsulate therapeutic agents. In psoriasis treatment, liposomes enable the targeted delivery of medications to affected skin layers, thereby improving drug penetration and reducing adverse effects. This targeted approach enhances therapeutic efficacy while minimizing systemic exposure. The present study addresses psoriasis, a chronic inflammatory and angiogenic skin disorder, by developing a docetaxel-loaded liposomes-in-gel (DTX-LP-G) system to improve the solubility and bioavailability of docetaxel. The optimized formulation, with a cholesterol to soy lecithin ratio of 1:5, achieved a particle size of approximately 143.37 nm and an encapsulation efficiency of about 88.5%. In vitro studies demonstrated sustained drug release (approximately 45.73% over 96 h), while ex vivo permeation studies showed significantly greater skin penetration (about 67.64%) compared to liposomes and gel alone (less than 20%). The system exhibited strong antioxidant activity, with over 90% hydrogen peroxide scavenging. In an imiquimod-induced psoriasis mouse model, DTX-LP-G significantly reduced erythema, scaling, skin thickness, and splenomegaly, as well as the oxidative stress marker malondialdehyde (MDA). Additionally, it downregulated key inflammatory and angiogenic mediators, including IL6, HIF-1α, and VEGF, and inhibited abnormal vascular proliferation, reducing vessel diameter from approximately 256 nm toward normal levels. These findings suggest that DTX-LP-G enhances transdermal delivery, provides sustained release, and exerts multi-target therapeutic effects, supporting its potential as an effective strategy for psoriasis treatment [33].

Ethosomes

Ethosomes are phospholipid based nanovesicles that enhance transdermal drug delivery by increasing skin permeability and fluidizing lipid bilayers. In psoriasis, ethosomes can overcome the thickened skin barrier, facilitate drug penetration into deeper skin layers and contribute to restoring lipid balance. These properties make ethosomes an effective carrier for topical therapy. A recent study developed a tryptanthrin-loaded ethosomal nanocarrier (Tryp-ES) to improve topical delivery for psoriasis, a chronic inflammatory skin disorder characterized by limited drug penetration. The optimized formulation, containing 30% propanediol, 10 mM DMPC and 0.03% LGS, produced stable vesicles measuring approximately 100–112 nm with a low polydispersity index (PdI) of about 0.22 and high entrapment efficiency (97.19 ± 2.95%). The system demonstrated controlled biphasic drug release (approximately 68.35% at 2 h and 71.95% at 48 h), while the gel form provided sustained release (58.15% at 48 h). In vitro studies showed enhanced cellular uptake and significant inhibition of keratinocyte proliferation (up to 41.3%) through apoptosis induction. Ex vivo experiments indicated superior skin retention (epidermis: 133.2 ng/cm²; dermis: 121.2 ng/cm²) and rapid permeation (1.43% within 30 min) compared to conventional formulations. In vivo, Tryp-ES significantly alleviated psoriatic symptoms by reducing epidermal hyperplasia, inflammation and angiogenesis without observable toxicity. Mechanistically, the ethosomal system transiently disrupted lipid bilayers to enhance penetration and subsequently restored membrane integrity. These findings suggest that Tryp-ES is a potent and safe nanotherapeutic platform for effective psoriasis management [34].

Niosomes

Niosomes are non-ionic surfactant vesicles that enhance topical drug delivery by improving skin penetration and enabling controlled release. In the context of psoriasis, niosomes increase drug retention within skin layers and improve therapeutic efficacy while reducing side effects. A recent study addressed psoriasis, a chronic inflammatory skin disorder affecting approximately 2–3% of the population, by developing a tacrolimus-loaded niosomal gel to improve topical delivery. Niosomes were prepared using the film hydration method with varying surfactant-to-cholesterol ratios (0.5:0.5 to 0.5:1.5), resulting in vesicles ranging from 67.8 to 121.6 nm in size. The optimized batch (NF5) demonstrated the highest drug content (99.2 ± 1.2 mg) and entrapment efficiency (98.68%). The selected formulation was incorporated into gels, with F5 and F6 exhibiting optimal clarity and spreadability, and F6 achieving the highest viscosity (8166 cPs). In vitro release studies were conducted for up to 48 h, and no skin irritation was observed in animal studies. In vivo evaluation indicated that the tacrolimus niosomal gel significantly reduced psoriasis severity, as evidenced by the lowest PASI score compared to controls. These findings suggest that niosomal gel enhances drug retention, penetration, and therapeutic efficacy, representing a promising strategy for topical psoriasis management [35].

Solid lipid nanoparticles (SLNs)

Solid lipid nanoparticles (SLNs) are lipid-based nanocarriers that enhance topical drug delivery by improving skin penetration, stability, and controlled release. In the context of psoriasis, SLNs facilitate the penetration of drugs through the thickened stratum corneum, increase drug retention in deeper skin layers, and reduce inflammation, thereby representing an effective strategy for targeted therapy. A recent study addressed psoriasis, a chronic inflammatory skin disorder with an approximate prevalence of 2%, by developing noscapine-loaded solid lipid nanoparticles (SLN-NOS) to address poor solubility and limited skin penetration. The optimized SLN-NOS 1% formulation, prepared using high-shear homogenization, exhibited a particle size of approximately 245.66 ± 17 nm, a zeta potential of − 35.74 ± 2.59 mV, a polydispersity index (PDI) of 0.226, and a high encapsulation efficiency of 89.77%. In vitro release studies demonstrated enhanced drug release (83.23% at pH 5.8 compared to 58.49% at pH 7.4 over 72 h), while ex vivo studies indicated significantly higher skin accumulation (46.88% for SLN-NOS versus 13.5% for cream). In vivo, using an imiquimod (IMQ)-induced model, SLN-NOS 1% markedly reduced the Psoriasis Area and Severity Index (PASI) score (approximately 7 versus 9.4 in IMQ), ear thickness, and inflammation. The formulation also significantly decreased pro-inflammatory cytokines (TNF-α, IL-17, TGF-β) and increased the anti-inflammatory cytokine IL-10. Histological analysis confirmed reduced hyperkeratosis and epidermal thickening. Collectively, SLN-NOS demonstrated superior skin penetration, sustained drug release, and anti-inflammatory efficacy, indicating its potential as a promising nanocarrier for effective topical psoriasis therapy [36] (Fig. 1).

Fig. 1.

Lipid based nanocarrier systems used in topical psoriasis therapy

Polymeric nanosystems

Polymeric systems offer controlled release, targeting, and stimuli-responsive mechanisms. Main systems include Dendrimers, Nanogels, and Nanocapsules.

Dendrimers

Dendrimers are highly branched nanoscale polymers characterized by well-defined structures and multiple functional surface groups. This architecture facilitates efficient drug loading, targeted delivery, and controlled release. Consequently, dendrimers represent promising carriers for drug delivery and biomedical applications. A recent study investigates dendrimer-based topical therapy for psoriasis utilizing IMD-006 and its stable analogues (IMD-036, IMD-046). Dendrimers were encapsulated within TriCat catanionic vesicles and incorporated into xanthan hydrogel to improve stability and facilitate skin delivery. The vesicles demonstrated high drug loading (approximately 70–80%) and enhanced skin retention (about 30 µg compared to 9 µg for the free drug), with deeper tissue penetration. In a psoriatic mouse model, TriCat/IMD-006 treatment significantly reduced disease severity (clinical score 5.7 versus 9.6; histological score 10.4 versus 16.4, p < 0.0001). The formulation at 13 mg/kg achieved efficacy comparable to higher-dose free drug and corticosteroids. These findings indicate that vesicle-based delivery improves anti-psoriatic efficacy and represents a promising topical therapeutic alternative [37].

Nanogels

Nanogels are nanosized, three-dimensional polymeric networks that can retain substantial quantities of water while encapsulating therapeutic agents. These structures improve drug solubility, stability, and facilitate controlled release, which increases their effectiveness for topical and transdermal drug delivery. Additionally, their small size and high biocompatibility promote enhanced skin penetration and enable targeted therapeutic interventions. Recent study investigates psoriasis, a chronic inflammatory skin disorder, with the objective of improving treatment through the use of tapinarof-loaded nanogels to enhance drug delivery and efficacy. Nanogels were prepared using self-nanoemulsifying drug delivery systems (SNEDDS) and carbopol-based matrices, and evaluated by dynamic light scattering (DLS) for particle size, MTT assay for cell viability, rheology, texture analysis, in vitro drug release, and wound healing assays. The resulting formulations demonstrated nanoscale particle size (approximately 150 nm), good stability, and non-toxicity to HaCaT cells, maintaining over 70% viability. In vitro release studies revealed that nanogel II achieved superior drug release (approximately 81% in 5 h) compared to nanogel I (approximately 52%). Rheological analysis confirmed appropriate viscosity and spreadability for topical administration. Wound healing assays indicated enhanced antiproliferative and antimigratory effects of tapinarof in nanogel form. The formulations also exhibited controlled and sustained drug release profiles. In summary, tapinarof nanogels substantially improve bioavailability, safety, and therapeutic efficacy, supporting their potential as promising candidates for topical psoriasis therapy [38].

Nanocapsules

Nanocapsules are nanoscale drug delivery systems composed of a polymeric shell that encloses a liquid or solid core containing the active pharmaceutical ingredient. These systems enhance drug stability, protect labile molecules and enable controlled as well as targeted release. The small size and high surface area of nanocapsules facilitate improved skin penetration, thereby increasing their efficacy in topical therapeutic applications. Recent study seeks to improve psoriasis treatment by developing a pectin-based hydrogel loaded with tacrolimus nanocapsules (PEC-NCtac) to enhance targeted topical delivery. The formulation was prepared by incorporating polymeric nanocapsules into a pectin hydrogel and was evaluated through physicochemical characterization, cytotoxicity assays, adhesion studies, skin permeation analysis, and anti-inflammatory testing. The nanocapsules exhibited a nanoscale size of approximately 250 nm, high drug content (approximately 0.81 mg/g), and nearly 100% cell viability, indicating favorable safety. PEC-NCtac significantly reduced IL-17A levels (p < 0.05), demonstrating anti-inflammatory activity. Adhesion studies indicated enhanced skin adherence, with a 1.9-fold increase compared to hydrogel alone, supporting prolonged drug contact. Skin permeation studies demonstrated controlled delivery with reduced epidermal permeation (40% compared to 70% for commercial ointment). The formulation was non-irritant and showed superior anti-inflammatory efficacy (75% compared to 58%). Collectively, PEC-NCtac demonstrates improved safety, adhesion, and therapeutic performance, suggesting its potential as a promising topical strategy for psoriasis treatment [39, 40] (Fig. 2).

Fig. 2.

: Polymeric nonsystem

Hybrid and emerging nanotechnology platforms

This category combines lipid, polymer, and device assisted strategies to enhance therapeutic precision. Systems include Microneedle, Nanoemulsion, Nanosponges and Electrospun Nanofiber-Based Drug Delivery Systems.

Microneedle

Microneedles are minimally invasive transdermal drug delivery systems composed of small needle-like structures that create microchannels in the skin. These devices facilitate painless and targeted drug delivery directly into the epidermis or dermis, which improves drug bioavailability, reduces systemic side effects, and enhances patient compliance. Recent research evaluated polymeric dissolving microneedles as a novel transdermal strategy for psoriasis treatment, utilizing secukinumab (an IL-17A inhibitor) and Stattic (a STAT3 inhibitor). The microneedles were fabricated from hyaluronic acid and sucrose using micro-molding techniques and assessed through in vitro characterization, cytotoxicity assays, ex vivo penetration studies, and in vivo experiments in a psoriasis mouse model. The microneedles exhibited sufficient mechanical strength (resistance of approximately 14.34 N) and effective skin penetration (approximately 400 µm depth). Drug release studies demonstrated complete release within 120 min, following Weibull kinetics. Cytotoxicity assays indicated good biocompatibility, with cell viability exceeding 80%. In vivo results revealed that secukinumab-loaded microneedles significantly reduced inflammation and necrosis compared to controls, while combination therapy provided less benefit. Immunological analysis confirmed reduced IL-6 levels and STAT3 inhibition. Overall, secukinumab-loaded microneedles offer a safe, effective, and minimally invasive approach for targeted psoriasis therapy [41].

Nanoemulsion gel

Psoriasis is a long-lasting inflammatory skin disease caused by immune system problems and too much growth of skin cells. Dithranol is a proven treatment, but it often causes irritation and does not penetrate the skin well. Recent study formulated a dithranol nanoemulsion gel using high-speed mixing and ultrasound, then tested its properties and effects in a mouse model of psoriasis. The best version had a particle size of about 176 nm, a low PDI of 0.189, high stability at 41.7 mV, released the drug steadily for up to 300 min, and was well tolerated. Tests on animals showed it lowered PASI scores, redness, and skin thickness without causing irritation. Overall, the nanoemulsion gel improved how the drug moved through the skin, worked better, and caused fewer side effects, showing promise as a new topical treatment for psoriasis [42].

Nanosponges

Nanosponges are nanosized, porous polymeric carriers with a three-dimensional network that can encapsulate both hydrophilic and lipophilic drugs. These carriers improve drug solubility and stability and enable controlled or sustained release. Their high surface area and porous structure support enhanced topical drug delivery and increased skin retention. A recent study addressed psoriasis, a chronic immune-mediated inflammatory skin disorder, by developing a berberine-loaded nanosponge-based hydrogel to improve topical delivery. Nanosponges were synthesized using β-cyclodextrin and incorporated into a chitosan–propolis hydrogel, followed by comprehensive physicochemical and in vivo evaluation. The optimized formulation exhibited a nanoscale size (42.1 nm), a very low polydispersity index (0.003), a zeta potential of − 11.8 mV, and high entrapment efficiency (~ 77%). The hydrogel demonstrated suitable rheological properties and achieved approximately 2.5-fold higher skin deposition compared to a conventional gel. In vivo studies indicated significant improvement in psoriasis symptoms, including reduced scaling, inflammation, and hyperkeratosis. Biochemical analysis showed an approximate twofold reduction in IL-23, IL-17A, and MDA levels (p ≤ 0.001). The formulation also inhibited chemerin and MAPK pathways, indicating a potential novel mechanism of action. In summary, the nanosponge-based hydrogel improves drug delivery and efficacy and represents a promising topical therapy for psoriasis [43].

Electrospun nanofiber-based drug delivery systems

Electrospun nanofiber systems have recently gained attention as new options for localized and sustained topical drug delivery in psoriasis treatment. In one study, researchers developed patches loaded with methotrexate (MTX) using polymeric materials made of polycaprolactone (PCL), Eudragit L100, and their combination to improve the delivery of MTX as a first-line drug for psoriasis. Researcher created the nanofibrous patches with an electrospinning method and then analyzed their morphology, physical properties, and mechanical characteristics. Scanning electron microscopy (SEM) showed uniform fiber shape and diameter distribution at the nanoscale. Thermal tests using thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) indicated good thermal stability for the formulations. X-ray diffraction (XRD) studies also showed that MTX was dispersed in a non-crystalline state within the polymeric materials, suggesting better drug distribution and stability. Additional tests included wettability analysis through water contact angle measurements, tensile strength testing to assess mechanical stability, and checking the efficiency of drug encapsulation. In vitro drug release tests showed a controlled and sustained release profile of methotrexate from the nanofiber systems. Among the formulations tested, the Eudragit L100-PCL composite nanofiber patch demonstrated better mechanical properties and improved drug release compared to single-polymer systems. Ex vivo skin permeation studies confirmed that this optimized formulation allowed for better MTX penetration through the skin barrier. The controlled-release nanofibrous patch thus provides improved local drug delivery while reducing systemic exposure linked to traditional oral methotrexate therapy. Overall, these results suggest that MTX-loaded electrospun nanofiber patches represent a promising new approach for sustained topical treatment of psoriatic plaques, potentially enhancing therapeutic effectiveness while minimizing systemic side effects [44] (Tables 2, 3; Fig. 3).

Table 2.

Summary of nanocarrier systems for psoriasis

Nanocarrier type	Representative drugs	Key mechanism	Evidenced benefits	Stage
Liposomes-in-gel	Docetaxel	Lipid bilayer fusion with gel-mediated controlled release and modulation of IL6–HIF-1α–VEGF axis	Enhanced skin penetration, sustained release, reduced MDA levels, inhibition of angiogenesis and inflammation	Preclinical [33]
Ethosomes	Tryptanthrin	Lipid bilayer fluidization and vesicle deformability enabling deep skin penetration and membrane disruption	Rapid skin permeation within 1 h, enhanced cellular uptake with nuclear localization, inhibition of keratinocyte proliferation via apoptosis, reduced inflammation and angiogenesis, improved psoriasis symptoms without toxicity	Preclinical [34]
Niosomes	Tacrolimus	Non-ionic surfactant vesicles improving drug encapsulation and controlled release, enhancing skin permeation and retention	Nanosized vesicles showed high drug content and entrapment efficiency, with good viscosity and spreadability. The formulation effectively reduced PASI score without causing skin irritation	Preclinical [35]
SLN	Noscapine	Lipid-based nanosystem enhancing skin penetration, occlusive film formation, and controlled drug release	Particle size ~ 245 nm, high entrapment, improved skin deposition, higher release, significant reduction in PASI, ear thickness, IL-17 and TNF-α levels	Preclinical [36]
Dendrimers	IMD-006, IMD-036 dendrimers	Vesicle membrane fusion enhances cellular uptake and dermal penetration; hydrogel enables sustained release and stability	Increased skin retention (2–3 ×), deeper epidermal/dermal penetration, sustained release up to 96 h, reduced psoriasis severity with efficacy comparable to corticosteroids	Preclinical [37]
Nanogels	Tapinarof	3D hydrophilic polymeric network enhances solubility, skin hydration, and permeation; activation of AhR pathway reducing IL-17/IL-22 cytokines and oxidative stress	Improved drug release, enhanced antiproliferative and antimigration activity, good biocompatibility on HaCaT cells, improved bioavailability and skin penetration	Preclinical [38]
Microneedle-NP	Secukinumab, Stattic	Transdermal delivery via skin microchannels; localized delivery to psoriatic plaques; IL-17A inhibition (secukinumab) and STAT3 pathway inhibition (Stattic); controlled dissolution of polymer matrix enabling drug release	Effective skin penetration (≈400 µm depth reaching epidermis), complete drug dissolution within ~ 120 min, high biocompatibility (> 80% cell viability), reduced inflammation and necrosis (especially with secukinumab alone), improved therapeutic efficacy at lower doses, targeted delivery with minimal systemic effects	Preclinical [41]
Nanoemulsions	Dithranol	Nanosized oil-in-water droplets enhance skin permeation and retention; improved drug solubilization with sustained release from gel matrix	Improved skin penetration, controlled release (~ 300 min), reduced PASI score, erythema, and skin thickness; minimized irritation and improved tolerability	Preclinical [42]

Table 3.

Comparative analysis of nanocarrier classes

Class	Key strengths	Limitations	Best suited drugs	Stage
Lipid-based	Excellent SC penetration, natural compatibility	Stability issues, limited loading for hydrophilic drugs	MTX, calcipotriol, acitretin	Preclinical → clinical [33]
Polymeric	Controlled release, targeting, stimuli-responsiveness	Expensive materials, complex synthesis	Tapinarof, corticosteroids	Mainly preclinical [37]
Hybrid/emerging	Deep penetration, high payloads, device-assisted delivery	Higher cost, regulatory complexity	Tacrolimus, Clobetasol-calcipotriol	Preclinical → early clinical [41]

Fig. 3.

Emerging drug delivery

Mechanistic basis of nanocarrier-enhanced skin delivery in psoriasis

Nanocarriers enhance dermal and transdermal delivery through penetration enhancement, localization, stratum corneum bypass, controlled release, and stabilization of labile compounds. Psoriatic skin exhibits several unique changes that include hyperkeratosis, disorganization of the lipid structure, increased inflammatory compounds, and changes in pH. Modern nanosystems have been designed to take advantage of these pathological changes to enhance the delivery and efficiency of drugs.

1. Penetration Enhancement

Liposomes and niosomes

These vesicular systems possess flexible phospholipid or surfactant-based bilayers that can interact with stratum corneum lipids. Fusion of their bilayers with epidermal lipids transiently disrupts the barrier, increases fluidity, and forms micro-channels, thereby enhancing drug permeation [45].

Ethosomes

These have high concentrations of ethanol, which fluidizes and disorganizes the tightly packed lipids in the stratum corneum, thereby allowing deeper penetration, even through hyperkeratotic psoriatic plaques [44].

Nanoemulsions

Due to their extremely small size, the droplets in nanoemulsions are conducive to the rapid diffusion of the drug through the layers of the skin due to their high interfacial surface area, characterized by diameters of less than 100 nm [46].

SLN and NLC

The reason being that the lipid composition of SLN and NLC is highly compatible with skin lipids, enhancing passive diffusion and hence promoting stronger deposition within the stratum corneum and upper epidermis [43].

• 2.Targeting Inflamed Psoriatic Tissues

Dendrimers

The multivalent and highly charged dendrimer surface enables electrostatic binding to negatively charged inflammatory skin component targets due to inflammation, thereby improving binding in psoriatic lesions [47].

ph-responsive nanogels

Psoriatic skin exhibits a slightly acidic pH (approximately 4.4). pH-responsive nanogels swell under this condition, enabling localized drug release specifically within inflamed plaques [48].

Nanosponges

Their porous, crosslinked structure holds drugs for long periods, which can then be released for sustained periods of time to areas of heightened inflammation [49].

• 3.Stratum Corneum Bypass

Microneedles

The microneedle arrays create small channels of about 150–300 μm in depth, which effectively circumvent the SC barrier, and the drug thus enters the viable epidermis or superficial dermis, the site of the inflammation process [50]

• 4.Sustained and Controlled Release

SLN and NLC

The solid lipid cores that make up the system provide a hard matrix for the drugs, hindering them from diffusing. This reduces the frequency of application for psoriatic plaques [43].

Nanocapsules

The "reservoir-type" carriers have the drug contained within a polymeric cover. This avoids the "burst" effect, reduces irritation, and maintains the long-term availability of the drug for therapeutic use [51].

• 5.Improved Stability of Labile Drugs

Cyclodextrin-based nanosponges

In their presence, their structures of inclusion and sponges shield fragile molecules like retinoids and psoralens against photodegradation or oxidation [49].

Dendrimers

The internal cavities and the functionalities at the dendrimer surfaces effectively protect the entrapped drugs against enzymatic degradation and oxidation [47].

Clinical applications and translational progress

Only a small number of formulations based on nanotechnology have advanced to human evaluation, despite their strong preclinical success in treating psoriasis. This section makes a clear distinction between approved dermatology nanomedicines, clinical trial results, and preclinical evidence [52–54].

Clinical trials of nanotechnology systems for psoriasis

Few nanocarrier-based formulations have reached human studies, but available trials demonstrate meaningful therapeutic benefits (Table 4).

Table 4.

Approved nanotechnology-based dermatology products

Product/technology	Active drug	Nanocarrier type	Indication	Development stage
Ameluz®	5-ALA	Nanoemulsion gel	Actinic keratosis	FDA/EMA approved [55]
Ambisome®	Amphotericin B	Liposomal formulation	Systemic fungal infections	FDA approved [56]
Azzalure®/Dysport®	Botulinum toxin	Nanocomplex	Dermatology/cosmetic	Approved [57]
Nanocort® (clinical-stage)	Corticosteroid	Liposomes	Skin inflammation	Near approval [58]
Nano-liposomal Dexamethasone Hydrogel	Dexamethasone	Liposomes	Inflammatory skin diseases	Preclinical/translational [34]
Methotrexate NLC Gel	Methotrexate	Nanostructured lipid carriers	Psoriasis	Phase II clinical study[59]
Tacrolimus SLN Ointment	Tacrolimus	Solid lipid nanoparticles	Psoriasis/dermatitis	Clinical evaluation [45]
Dendrimer-Etanercept Gel	Etanercept	Dendrimer-based carrier	Localized psoriasis	Phase I/II exploratory study [37]
Microneedle MTX Patch	Methotrexate	Microneedle-assisted nanoparticle delivery	Psoriasis	Preclinical [35]
Tacrolimus Nanocrystal Patch	Tacrolimus	Nanocrystal microneedle system	Psoriasis	Preclinical [41]
Clobetasol-Calcipotriol Nanoemulsion Gel	Clobetasol + Calcipotriol	Nanoemulsion	Psoriasis	Preclinical [42]
Tapinarof Nanogel	Tapinarof	pH-responsive nanogel	Psoriasis	Preclinical [38]

Methotrexate nanostructured lipid carriers (NLCs)

An MTX-loaded nanostructured lipid carrier (NLC) gel and a traditional methotrexate cream were compared over an 8 week treatment period in a randomised, parallel arm Phase II clinical trial with 60 participants. With a 60% decrease in PASI scores as opposed to the control group's 35% (p < 0.01), the NLC formulation showed noticeably better therapeutic efficacy. A better safety profile was indicated by pharmacokinetic evaluations, which verified reduced systemic methotrexate exposure in the NLC arm along with fewer hepatic enzyme elevations. Higher satisfaction ratings were also reported by patients using the NLC gel which is indicative of improved clinical results and tolerability. However, the study's short duration, small sample size, and lack of long-term relapse evaluation limit its interpretation [60, 61].

Tacrolimus solid lipid nanoparticle (SLN) ointment

Over the course of six weeks a solid lipid nanoparticle (SLN) based tacrolimus formulation and the conventional 0.1% tacrolimus ointment were compared in a clinical study involving fifty patients with mild-to-moderate psoriasis. Because of its better skin retention and controlled release behaviour, the SLN formulation achieved comparable clinical efficacy even though it contained only half the drug concentration. Better tolerability and spreading properties were demonstrated by the patients decreased application frequency, decreased local burning sensation, and more even drug distribution throughout psoriatic plaques. However, the short follow-up period, lack of comparisons with systemic calcineurin inhibitors and lack of plaque thickness standardisation limit the study's conclusions [62, 63].

Dendrimer etanercept topical gel

Over the course of four weeks, a Phase I/II exploratory study assessed a topical dendrimer-bound etanercept formulation in 24 patients with localised psoriatic plaques involving ≤ 10% body surface area. Effective localised TNF-α pathway suppression was demonstrated by the treatment's 50% reduction in local IL-17A expression and noticeable improvements in plaque thickness and scaling. ELISA confirmed that systemic absorption was minimal, and the topical route totally circumvented the injection related side effects that are commonly linked to subcutaneous etanercept. Despite these encouraging results, the study's limitations include its small sample size, its focus on localised disease, and the inability of topical dendrimer-etanercept to replace systemic biologics for moderate-to-severe psoriasis [64, 65].

Preclinical pipelines with high translational potential

Microneedle based methotrexate (MTX) delivery

In IMQ-induced psoriatic mouse models, microneedle based methotrexate (MTX) delivery systems have demonstrated a clear superiority over oral MTX, achieving stronger local anti-inflammatory effects with significantly reduced systemic liver toxicity. These systems present a viable path to increase safety and adherence by permitting targeted intradermal deposition and reducing gastrointestinal and hepatic exposure. When compared to conventional oral regimens, their minimally invasive, patch based design also suggests improved patient compliance. However, thorough sterility validation, pain perception evaluation, and proof of consistent performance across a range of skin types are necessary for successful clinical translation [66, 67].

Nanocrystal tacrolimus patches

Nanocrystal based tacrolimus microneedle patches have demonstrated markedly improved dermal delivery, achieving nearly six-fold higher skin deposition compared with conventional tacrolimus ointment. This enhanced penetration translated into effective normalization of key inflammatory cytokines in psoriatic animal models, underscoring their therapeutic potential. The system offers targeted delivery with reduced surface barriers, making it a promising alternative to traditional topical calcineurin inhibitors. However, translational progress is contingent on resolving challenges related to dose uniformity across microneedle arrays, which is critical for consistent clinical performance [68] (Table 5).

Table 5.

Comparative clinical relevance across systems

Formulation	Drug	Study type	Key outcome	Limitation
NLC Gel	MTX	Phase II	60% PASI reduction	8 week study
SLN Ointment	Tacrolimus	Phase II	Efficacy at 50% lower dose	Small sample [52]
Dendrimer Gel	Etanercept	Phase II (local lesions)	50% ↓ IL-17A	Limited BSA [54]
MN–NP System	MTX	Preclinical	Strong anti-inflammatory effect	No human studies [56]
Nanocrystal Patch	Tacrolimus	Preclinical	6 × higher deposition	Scalability [58]
NE Gel	Clobetasol + Calcipotriol	Preclinical	Rapid plaque reduction	No clinical trial [42]
pH Nanogels	Tapinarof	Preclinical	Epidermal normalization	Toxicity unknown [38]
β-CD NS Gel	COX-2 inhibitors	Early clinical	Improved retention	Long-term data lacking [59]

Limitations across clinical studies

Among the clinical studies available that have investigated nanotechnology based therapies for psoriasis, certain crucial limitations have been identified. The majority of studies have small sample sizes (≤ 60 patients) and short treatment periods of only 4–8 weeks, which are insufficient to properly evaluate a chronic and relapsing disease such as psoriasis. The results are also commonly expressed only in terms of PASI or BSA, without much emphasis on more general, patient-oriented scales such as Dermatology Life Quality Index (DLQI). Long-term safety, cost-effectiveness, and reproducibility of production are also not considered, and few studies are comparative with existing biologic or systemic therapies. Moreover, crucial subgroups of patients such as children, scalp or palmoplantar psoriasis, and nail psoriasis are also not considered. Taken together, these findings indicate that, despite the clear mechanistic advantage, nanotechnology based dermatologic therapies are still in the early stages of clinical validation and require larger, multi-center, long-term studies to properly establish their therapeutic value [52–54].

Manufacturing and scale-up challenges of topical nanomedicines

Formulations based on nanotechnology demonstrate superior laboratory results, but their successful commercialization is greatly dependent on manufacturability, reproducibility of batches, GMP compliance, and regulatory acceptance. Scaling up nanosystems from milligram to kilogram amounts is fraught with complexities of physicochemical, economic, and regulatory natures, which are not encountered in conventional topical formulations. This section will elaborate on the practical hurdles and provide industry examples [69–71].

Physicochemical and process related challenges

Maintaining particle size and PDI at large scale

It becomes challenging to maintain a consistent particle size, PDI value (< 0.3), zeta potential, and encapsulation efficiency (> 70%) during scaling up due to the high sensitivity of these factors to changes in homogenization pressure and batch size. Small changes may lead to an increase in particle size, instability, or a decrease in drug loading.

Industrial example:

Liposomal amphotericin B (AmBisome®) required > 10 years of optimization due to scale-dependent shifts in vesicle size and lipid bilayer uniformity.

Process transfer: lab versus manufacturing

Scale up of the process from the lab to manufacturing introduces a large variability because of the replacement of small equipment such as probe sonicators, small volume homogenizers and magnetic stirrers with high-pressure homogenizers, microfluidizers, and continuous mixers. This leads to a large variability in the shear rates, cavitation forces, and heat generation, which are critical factors in determining the size of the particles and PDI.

Stability during storage

However, topical nanocarriers can be prone to Ostwald ripening, particle aggregation, drug leakage, lipid oxidation, and polymer degradation. These problems can be overcome by the addition of cryoprotectants, antioxidants, and viscosity modifiers. These additives can help to maintain the integrity of the particles and prevent deterioration due to chemical or physical changes.

Sterility requirements

Sterility is a major requirement for microneedles, nanogels, and ocular nanocarriers, requiring aseptic filling processes, Grade A/B cleanroom facilities, and formulations that are compatible with the process of sterile filtration. Unfortunately, many nanoparticle formulations are not suitable for filter sterilization based on particle size, making aseptic processing and control of the process critical for microbial safety.

Reproducibility and batch-to-batch variability

Maintaining reproducibility in terms of physicochemical properties among batches is another important challenge associated with nanocarriers. It is apparent that slight changes in the rate of mixing, solvent evaporation rate, homogenization pressure, and temperature can cause substantial changes in the size distribution of particles, drug loading, and release profiles. Hence, it is important to incorporate strict control measures and real-time monitoring techniques to maintain reproducibility during large-scale manufacturing processes.

Analytical characterization limitations

Advanced analytical tools that can be used to properly define nanocarrier systems include dynamic light scattering, transmission electron microscopy, atomic force microscopy, and differential scanning calorimetry. However, standardized analytical tools for nanomedicines are still under development, and different analytical tools may yield different results with regards to the size or stability of the nanocarrier systems.

Drug loading and encapsulation efficiency at large scale

It is often easier to attain high drug loading and encapsulation efficiency at the laboratory scale compared to the large scale. With the increase in batch size from the laboratory to the industrial scale, there is a possibility of drug leakage or reduced encapsulation efficiency due to changes in hydrodynamic conditions, which may affect the therapeutic dose of the drug. These issues necessitate the optimization of formulation parameters.

Long-term storage and shelf-life stability

Long-term stability of nanocarriers is a major challenge that hinders the successful commercialization of nanocarriers. For the lipid-based nanocarriers, the major problem that can be encountered during storage includes lipid oxidation, polymorphic transitions, or drug expulsion. For the polymeric nanoparticles, degradation of the polymer or aggregation of the nanoparticles can be a problem. This can affect the stability of the drug. Thus, a certain level of stabilization of the product, such as lyophilization or the use of cryoprotectants, is required [72].

Good manufacturing practice (GMP) requirements for nanocarriers

GMP for nanocarrier-based products demands more rigorous control compared to conventional topical products. Cleanroom classification for production facilities should be appropriate, with liposomes, SLNs, and microneedles being manufactured in Grade C/D cleanrooms, while nanoparticle-loaded microneedle patches require Grade A/B cleanroom conditions for filling and drying. All equipment should be fully IQ/OQ/PQ qualified, as unqualified equipment has contributed to past regulatory issues, including EU suspensions of nanoparticle oncology products because of inconsistent critical quality attributes. Moreover, the use of validated analytical procedures, such as DLS, TEM/SEM, DSC/TGA, and ICP-MS, is necessary to ensure accurate and consistent characterization of particle size, morphology, thermal properties, and elemental impurities [70, 73, 74].

Quality-by-design (QbD) for nanotechnology

Quality by Design (QbD) represents a systematic methodology for the rational development of nanotechnology-based drug delivery systems. International organizations, including the FDA and EMA, advocate for the implementation of QbD principles in drug delivery system development, as outlined in the International Conference for Harmonisation (ICH) guidelines Q8, Q9, and Q10. The QbD approach is particularly significant in the formulation of topical nanotechnology-based drug delivery systems for psoriasis, where it is essential for identifying key formulation factors that influence nanocarrier system performance [27, 75–77]. The initial step in the Quality by Design (QbD) approach involves identifying the Quality Target Product Profile (QTPP), which is essential for developing an effective drug delivery system. In the context of nanotechnology-based drug delivery systems for topical treatment of psoriasis, the QTPP guides the determination of key system characteristics, including drug delivery to the skin, systemic exposure, rheological properties, long-term stability, and user-friendliness. Furthermore, the identification of Critical Quality Attributes (CQAs) is a crucial component of the QbD approach for successful drug delivery system development [78–82]. Critical Quality Attributes (CQAs) are essential for evaluating the performance of drug delivery systems. Key CQAs include particle size, particle size distribution, polydispersity index (PDI), zeta potential, drug loading capacity, drug encapsulation efficiency, and drug release profile. These attributes influence factors such as drug delivery to the skin, release kinetics, long-term stability, and usability. To assess the impact of Critical Material Attributes (CMAs) and Critical Process Parameters (CPPs), statistical tools such as Design of Experiments (DoE) are employed. Experimental designs, including Factorial Designs, Box-Behnken Designs, and Central Composite Designs, facilitate the identification of optimal formulation conditions while minimizing experimental workload. These approaches enable the development of a Design Space, within which processes can be controlled to achieve the desired product quality. Risk assessment is another important component of Quality by Design (QbD) implementation and can be conducted using tools such as Failure Mode Effects Analysis and Ishikawa Diagrams to identify high-risk variables affecting product quality. Finally, maintaining CQAs within specified limits requires the implementation of a robust control strategy. Applying QbD principles to the development of nanotechnology-based topical formulations ensures that nanomedicine products for psoriasis treatment are produced with high quality and in compliance with regulatory standards [83, 84] (Table 6).

Table 6.

Example QbD elements for topical nanocarrier development [83, 84]

QbD element	Example in psoriasis nanocarriers
QTPP	Localized skin delivery, minimal systemic exposure
CQA	Particle size, PDI, encapsulation efficiency
CMA	Lipid/polymer composition, surfactant concentration
CPP	Homogenization pressure, sonication time
Risk Assessment	FMEA analysis of process variables
Design Space	Optimal range of formulation variables

Industrial example:

Gattefossé used QbD to optimize SLN formulations with repeatable CQAs across pilot and commercial scales.

Real world industrial challenges

The development of nanomedicines as topical formulations is hampered by several issues. The variability of raw materials is still a concern, as high-purity phospholipids, PEG-lipids, cyclodextrins, and medical-grade polymers are expensive and sometimes in short supply, with lipids alone accounting for over 40% of the total production costs. The scale-up of microneedle-based formulations also poses several issues, such as maintaining the integrity of the mold, ensuring homogeneous drug loading, achieving sterile drying conditions, and reducing patch-to-patch variability. In terms of regulatory issues, nanomaterials are required to meet more stringent toxicological standards than conventional topical formulations, requiring assessments for dermal repeated dose toxicity, nanoparticle biodistribution, long-term polymer degradation, phototoxicity, and genotoxicity [85, 86].

Regulatory hurdles specific to topical nanomedicines

The regulatory pathways for topical nanomedicines in psoriasis have specific requirements set by organizations such as the FDA, EMA, and CDSCO. The primary emphasis is on skin penetration and depth of delivery characterization, where the regulatory authority demands ex- vivo human skin permeation studies, confocal imaging, and dermatokinetic analysis to ensure targeted delivery in psoriatic lesions [87–89]. As psoriasis is characterized by the presence of inflamed and highly permeable skin, the regulatory authority demands nanoparticle accumulation studies, including the accumulation of nanoparticles in the diseased tissue, their entry into systemic circulation, or retention in the skin. Formulations with chemical penetration enhancers, such as ethosomes, transethosomes, and nanoemulsions demand strong irritation and sensitization data because of their high ethanol or surfactant concentration. Other requirements include photostability and light-sensitivity studies for compounds such as psoralens, retinoids, and curcumin, and comprehensive immunotoxicity profiling to assess cytokine modulation, immunosuppressive potential, and allergenicity in view of the immune-mediated pathogenesis of psoriasis. Finally, the regulatory authority demands the demonstration of batch-to-batch reproducibility of key critical quality attributes for at least three GMP batches, along with accelerated and long-term stability [90, 91].

Economic and cost-effectiveness limitations

However, economic and cost-effectiveness constraints continue to be significant hurdles in the widespread use of topical nanomedicines in psoriasis. The cost of production is significantly higher than that of conventional topical formulations, as nanocarriers may require high-shear mixers, microfluidic devices, sterile processing facilities, and in some cases, cryogenic storage, which increases operational costs [92]. Moreover, in developing countries such as India, Brazil, and certain areas of Indonesia, there is a lack of GMP compliant facilities for nanomedicine production. In addition, no clinical study has been conducted to explore cost-effectiveness, including the comparison of nanoformulations with conventional topical formulations, cost per unit PASI response, or relapse-related healthcare economics. This absence of economic modeling is a significant translational barrier that needs to be overcome before nanotechnology-based psoriasis therapies can be incorporated into mainstream clinical practice [93–95] (Tables 7, 8).

Table 7.

Manufacturing and regulatory challenges [61–65]

Challenge type	Specific challenge	Regulatory/clinical impact
Physicochemical	Maintaining particle size/PDI	Affects efficacy s stability
Material Variability	Lipid/polymer purity	Batch inconsistency
Sterility	MN and NP sterilization difficulty	Approval delays
Stability	Aggregation, drug leakage	Short shelf-life
QbD Gaps	Undefined CPP–CQA mapping	Higher rejection risk
Analytical Validation	Lack of standardized nanoparticle assays	Regulatory non-compliance
Toxicology	Need for dermal biodistribution data	Costly full studies
Economic	High manufacturing costs	Limited LMIC access

Table 8.

Manufacturing and regulatory challenges [66–68]

Challenge category	Specific issue	Impact on commercialization
Particle uniformity	Size/PDI shifts during scale-up	Inconsistent efficacy
Raw materials	High cost of lipids/polymers	Expensive final product
Sterility	Difficulty sterilizing MNs and nanoparticles	Regulatory delays
Stability	Aggregation, leakage	Short shelf-life
QbD gaps	Undefined CPP–CQA relationships	Batch failure risk
Regulatory	Lack of nanomedicine-specific guidelines	Additional data demands
Toxicology	Need for nanoparticle biodistribution studies	Higher cost + longer timelines
Economic	High capital investment	Limited LMIC adoption

Continuous manufacturing and process analytical technology (PAT) challenges

Traditional batch manufacturing of nanocarriers is inherently discontinuous and prone to inter-batch variability. The adoption of continuous manufacturing (CM) platforms, which are strongly supported by the FDA and EMA to enhance process consistency and reduce cycle times, introduces specific challenges for topical nanomedicines. Although microfluidic reactors and continuous high-pressure homogenization systems provide precise control over mixing conditions and residence times, their implementation in large-scale GMP facilities for nanocarrier production remains both technically and economically challenging.

Process Analytical Technology (PAT) tools, such as inline particle size analyzers including focused beam reflectance measurement (FBRM), real-time Raman spectroscopy, near-infrared (NIR) probes for drug content monitoring, and in-line viscometers, are increasingly required by regulatory agencies for nanomedicine manufacturing. Integrating these tools into nanocarrier production lines is technically challenging due to the nanoscale of the particles, the opacity of lipid-based formulations, and the necessity for probes that do not disrupt the formulation microenvironment during measurement. Calibration and validation of PAT tools across different batches and manufacturing platforms remain unresolved issues that hinder real-time release testing (RTRT), which is critical for reducing manufacturing timelines and costs in commercially scalable nanomedicine production [96].

Cold-chain logistics, packaging and distribution challenges

An often underappreciated challenge in topical nanocarrier based psoriasis treatments is ensuring formulation stability throughout the supply chain. Many lipid-based and polymeric nanocarriers are temperature sensitive and require storage at low temperatures, typically between 2 and 8 °C, or even freezing during shipping and storage. For instance, liposomal products such as AmBisome® require continuous cold-chain management, which increases overall costs and heightens the risk of product failure if the cold chain is disrupted at any stage from manufacturing to patient use.

Because psoriasis is a chronic condition that requires repeated topical treatment, reliance on cold-chain storage presents substantial challenges. These difficulties are especially acute in tropical regions, rural clinics, and low- and middle-income countries where reliable refrigeration is often lacking. The development of thermostable nanocarrier formulations, such as those produced by freeze-drying with cryoprotectants like trehalose or mannitol, or by spray-drying into reconstitutable powders, offers a promising but technically complex solution to this problem.

Selecting appropriate packaging for these formulations introduces additional challenges. Many nanocarrier-based topical gels are unsuitable for storage in standard aluminum tubes because metal ions may induce lipid oxidation. These formulations are also sensitive to light and therefore require opaque or amber packaging. The outer packaging must provide protection against moisture, which can accelerate undesirable changes in the product or degrade sensitive drug molecules. Ensuring compatibility between the formulation and packaging throughout the product’s shelf life necessitates specialized extractables and leachables (EandL) studies, thereby increasing both regulatory requirements and development costs [97].

Intellectual property, exclusivity and biosimilar nanocarrier barriers

Originator nanotechnology companies have developed comprehensive patent portfolios covering nanocarrier composition, manufacturing processes, defined critical process parameter (CPP) ranges, application devices, and specific therapeutic indications. Consequently, this has created a dense IP thicket that significantly restricts freedom to operate for subsequent manufacturers.

Unlike traditional small-molecule generics, which can demonstrate bioequivalence through standard pharmacokinetic studies, nanocarrier-based formulations are classified by the FDA and EMA as non-biological complex drugs (NBCDs), for which establishing bioequivalence is considerably more challenging. Currently, there is no clear regulatory framework for “nanosimilars,” in contrast to the established biosimilar guidelines for biologics. Consequently, generic entrants must conduct extensive and costly comparability studies, including physicochemical characterization, in vitro performance equivalence, and often additional clinical bridging studies [91]. These regulatory and IP barriers substantially reduce the incentive for generic manufacturers to develop nanocarrier-based psoriasis therapies, thereby limiting competitive pricing, market access, and long-term affordability, especially in price-sensitive healthcare systems such as those in India, Brazil, and Southeast Asia [98].

Limitations of current nanotechnology-based psoriasis therapies

Although substantial progress has been made, nanotechnology-based psoriasis therapies are still very distant from being commonly used in clinical practice because of a number of scientific, clinical, regulatory, and economic challenges [99]. The existing formulations are still plagued by a lack of understanding of skin-nanocarrier interactions, a lack of mechanistic validation, and primarily short-term safety data, raising questions about the long-term accumulation of nanoparticles, chronic inflammation, or sensitization. The preclinical assessment is largely dependent on the IMQ mouse model, which inadequately translates to human chronic plaque psoriasis, with no standardized biomarkers, making it difficult to compare across studies. In clinical settings, the trials are small (≤ 60 patients), of short duration, and rarely involve comparisons with biologics or systemic therapies, nor do they investigate hard-to-treat areas such as scalp, nail, or palmoplantar psoriasis. There are also manufacturing challenges because of the high cost of production, the lack of GMP nanomedicine facilities in LMICs such as India, and the difficulty in ensuring sterility for microneedles and nanoparticle gels. However, regulatory uncertainties still exist due to the lack of disease-specific nanomedicine guidelines from the Food and Drug Administration and European Medicines Agency, particularly concerning the classification and nanoparticle toxicity requirements. In terms of economic viability, the high cost of goods and the lack of reimbursement frameworks, especially in developing countries such as India or other LMICs, further hinder the commercialization process. Taken together, these factors underscore the fact that, despite the scientific merit of nanocarrier-based platforms, their translation into clinical reality will necessitate large, long-term multicenter studies and cost-effective manufacturing processes [94, 95, 100].

Future perspectives

Future growth in nanotechnology based psoriasis therapy will depend on the development of personalized nanomedicine platforms that can target lesions specifically, release drugs in response to biomarkers, and optimize particle size and penetration using AI. Extension of applications to challenging areas such as the scalp, nails, palmoplantar, and reverse skin will demand specific platforms that include nanoemulsion sprays, nanocrystal lacquers, high-pressure transethosomes, and low-irritancy nanogels. Newer theranostic nanocarriers that combine real time imaging with targeted drug delivery, such as fluorescently labeled pH-responsive nanogels or nanoparticle OCT contrast enhancers, may also improve the accuracy of treatment. Harmonization of regulations by the Food and Drug Administration and the European Medicines Agency, including the development of nanomedicine monographs, toxicity charts, and dermatology guidelines, will also facilitate progress. Environmentally sustainable and cost-effective manufacturing can be accomplished using microfluidic continuous reactors, solventless processes, and bio-derived lipids or polymers. From a clinical perspective, large multicenter studies involving ≥ 200 patients and long-term follow-up (6–12 months) will need to include PASI, DLQI, relapse rates, and head-to-head comparisons with biologics. Future approaches may also combine topical nanocarriers with systemic biologics or JAK inhibitors to decrease the systemic dose. To make it globally accessible, especially in the Indian subcontinent, commercialization will require simplified formulations, nano-GMP centers, and collaboration with the local pharmaceutical industry [91, 93, 101].

Conclusion

Nanotechnology has completely altered the psoriasis treatment landscape by offering novel solutions to the existing problems of low solubility, poor penetration of the hyperkeratotic stratum corneum, high drug degradation rates, and poor patient compliance. Lipid-based carriers, polymeric nanocarriers, microneedles, nanoemulsions, nanocrystals, and nanosponges have been shown to possess better pharmacokinetics and pharmacodynamics in preclinical studies, allowing for enhanced penetration, retention, and controlled release in the psoriatic microenvironment. Initial clinical trials, such as methotrexate-loaded nanostructured lipid carriers, tacrolimus solid lipid nanoparticles, and biologics conjugated with dendrimers, have shown encouraging results in terms of lowering PASI scores, minimizing systemic exposure, and improved patient tolerability compared to traditional formulations. These findings clearly indicate that nanotechnology-based topical formulations have the potential to fill the gap between topical creams with low efficacy and expensive biologics. However, despite its high scientific potential, the pace of translation is still slow. Challenges such as small sample sizes in clinical studies, short study periods, the absence of long-term safety information, and the complexity of manufacturing continue to hamper commercialization. The scale-up of nanomedicines demands high-quality Quality-by-Design approaches, sophisticated analytical validation, and GMP facilities that are not yet available in most parts of the world, especially in low- and middle-income countries. Looking ahead, the forthcoming decade is expected to see the advent of personalized nanomedicine, lesion-targeted drug delivery, and the incorporation of theranostic systems that track treatment responses in real-time. New technologies such as microneedle-assisted nanocarriers, peptide-targeted vesicles, and stimuli-responsive nanogels will move from the proof-of-concept stage in preclinical studies to well-powered Phase III clinical trials. At the same time, continuous manufacturing platforms, green synthesis approaches, and standardized global regulatory frameworks will make production easier, less expensive, and faster. Through continued innovation, collaboration, and investment in scalable manufacturing, nano-enabled therapies are poised to provide safer, more effective, and accessible treatment solutions for psoriasis. As the research continues to evolve and more clinical data becomes available, nanotechnology-based topical products could become the foundation of future psoriasis treatment, providing patients with better disease management and a reduced rate of relapse.

Abbreviations

8-MOP

8-Methoxypsoralen

AI

Artificial intelligence

ALA/5-ALA

5-Aminolevulinic acid

BSA

Body surface area

β-CD-NS

Beta cyclodextrin-based nanosponges

CCL17

Chemokine (C-C motif) ligand 17

CDSCO

Central Drugs Standard Control Organisation (India)

CETP

Cholesteryl ester transfer protein

CM

Continuous manufacturing

CMAs

Critical material attributes

Cmax

Maximum plasma concentration

CPPs

Critical process parameters

CQAs

Critical quality attributes

CVD

Cardiovascular disease

COX-2

Cyclooxygenase-2

DLQI

Dermatology life quality index

DoE

Design of experiments

DSC

Differential scanning calorimetry

EMA

European medicines agency

FDA

Food and Drug Administration (USA)

EMA

European Medicines Agency

EU

European Union

GBD

Global burden of disease

GMP

Good manufacturing practice

HaCaT

Human adult low calcium high temperature keratinocytes (immortalized cell line)

HPMC

Hydroxypropyl methylcellulose

ICPs

In-process controls

IL-17A, IL-23, etc.

Interleukin-17A, Interleukin-23

IMQ

Imiquimod

IMPD

Investigational medicinal product dossier

IPQC

In-process quality control

JAK

Janus kinase

LMIC

Low- and middle-income countries

LNC

Lipid nanocarrier

LOD

Limit of detection

MN

Microneedle

MTX

Methotrexate

MR

Modified release

NLC

Nanostructured lipid carrier

NMR

Nuclear magnetic resonance

NP

Nanoparticle

NS

Nanosponge

OCT

Optical coherence tomography

OQ

Operational qualification

PASI

Psoriasis area and severity index

PAT

Process analytical technology

PDI

Polydispersity index

PEG-DSPE

Polyethylene glycol–distearoylphosphatidylethanolamine

PIC/S

Pharmaceutical Inspection Co-operation Scheme

PK

Pharmacokinetics

PLGA

Poly(lactic-co-glycolic acid)

PQ

Performance qualification

PS

Particle size

pH-responsive

Potential of hydrogen responsive

PV

Process validation

QbD

Quality by design

QTPP

Quality target product profile

RONS

Reactive oxygen and nitrogen species

SC

Stratum corneum

SD

Standard deviation

SEM

Scanning electron microscopy

SLN

Solid lipid nanoparticle

TNF-α

Tumor necrosis factor-alpha

Treg

Regulatory T cells

UV

Ultraviolet

XRD

X-ray diffraction

Author contributions

Mr. Shritesh Bhoyar contributed to the conception of the review, performed the literature analysis, compiled preclinical and clinical data, prepared the mechanistic sections, figures, and tables, and wrote the first draft of the manuscript. Anil Pethe supervised the work, provided scientific and technical guidance, reviewed and edited the manuscript, validated the interpretations, and approved the final version for submission.

Funding

Open access funding provided by Datta Meghe Institute of Higher Education and Research. The Open access funding for this publication was Provided by Datta Meghe Institute of Higher Education and Research (DU), Wardha, Maharashtra.

Data availability

No datasets were generated or analysed during the current study.

Declarations

Ethics approval and consent to participate

Not applicable.

Consent to publish

All authors read and approved the manuscript for publication.

Competing interests

The authors declare no competing interest.