Research progress of penetration enhancers in transdermal drug delivery systems: Multidimensional exploration from mechanisms to clinical application

Abstract

Transdermal drug delivery systems (TDDSs) have gained significant attention in pharmaceutical research due to their ability to bypass hepatic first-pass metabolism, maintain consistent plasma drug levels, and improve patient compliance. Despite these advantages, the highly organized “brick-and-mortar” architecture of the stratum corneum (SC) poses a substantial barrier, particularly to the permeation of hydrophilic drugs and macromolecules. Among the strategies developed to address this challenge, penetration enhancers (PEs) have emerged as a key approach, offering reversible modulation of the skin barrier to improve drug transport. This review provides an in-depth analysis of the diverse mechanisms by which PEs facilitate transdermal delivery, including disruption of lipid bilayers, alteration of keratin structure, enhancement of drug partitioning into the SC, and lipid extraction. The crucial contribution of advanced characterization techniques, such as Fourier-transform infrared spectroscopy, Raman spectroscopy, and nuclear magnetic resonance, in revealing atomic-scale interactions between PEs and SC components is discussed.

Graphical abstract

1. Introduction

Transdermal drug delivery systems (TDDSs) provide a non-invasive modality for systemic drug administration by exploiting passive permeation across the skin barrier(Anjali and Sanchit, 2024; Niranjan et al., 2025). This approach bypasses hepatic first-pass metabolism, improving bioavailability and maintaining stable plasma concentrations(Han-Seong et al., 2020; Bajpai et al., 2022). TDDS offers the added advantage of enhancing patient adherence and can be adapted for the delivery of a wide range of therapeutic agents with minimal local irritation, establishing it as a valuable strategy in contemporary pharmacotherapy(Sanjivani et al., 2025; Peddapalli et al., 2024).

Despite these benefits, the clinical translation of TDDS is hindered by significant challenges, the most critical of which is the skin's barrier function(Phatale et al., 2022; Sintov, 2022). The structural and physiological characteristics of the skin impose strict limitations on drug permeation(Schafer et al., 2023). As the body's primary defensive interface, the stratum corneum (SC) is composed of densely packed keratinocytes embedded in a lipid matrix, forming a highly organized “brick-and-mortar” arrangement(Schafer et al., 2023; Zhang et al., 2023a). This architecture serves as a robust protective barrier, substantially restricting drug penetration into systemic circulation and consequently diminishing the therapeutic efficacy of transdermal formulations(Albayati et al., 2025; Cheng et al., 2023).

To address these limitations, multiple strategies have been explored, including the application of penetration enhancers (PEs)(Phaugat et al., 2023; Singh et al., 2024a), nanocarrier-based systems(Gomes et al., 2024; Ren et al., 2025), and physical enhancement techniques. Among these, PEs remain one of the most widely employed approaches in TDDS(Pereira et al., 2021). These agents function by reversibly altering the barrier properties of the SC, facilitating drug permeation (Kováčik et al., 2020). Their mechanisms of action encompass disruption of the lipid bilayer organization, modification of keratin conformations, enhancement of drug partitioning into the SC, and lipid extraction, ultimately improving the transdermal transport of therapeutic molecules.

Innovative nanocarriers have been developed to overcome limitations of conventional pharmaceuticals in TDDS, such as low solubility, limited permeability, poor stability, and reduced bioavailability(De Oliveira et al., 2022; Kaur and Muskan, 2024; Majumdar et al., 2024). Their impact on skin permeation depends on their composition and physicochemical properties. Lipid nanoparticles enhance hydration by forming an occlusive film on the skin(Shah et al., 2015), while polymer-based nanocarriers can efficiently penetrate via hair follicles(Desai et al., 2013). Among physical enhancement methods, iontophoresis(Buzia et al., 2023), electroporation(Yang et al., 2018), and sonophoresis(Polat et al., 2011) are widely applied, using external energy sources to transiently disrupt the SC and improve drug flux. Although effective in laboratory and preclinical studies, these approaches face clinical challenges, including safety, stability, biocompatibility concerns for nanocarriers, skin irritation, drug limitations, device dependency, and compliance issues for physical methods. By comparison, PEs can safely and reversibly modulate SC properties to improve cutaneous permeation, making them a promising strategy for TDDS(Kathuria et al., 2025; Mahapatra et al., 2023; Phatale et al., 2022). A combination of analytical techniques is essential to comprehensively decipher the multi-faceted mechanisms of PEs, with each method probing specific structural alterations within the SC(Phatale et al., 2022; Yadav et al., 2025). Spectroscopic methods, such as Fourier-transform infrared (FTIR) and Raman spectroscopy, are widely employed to reveal molecular-level interactions of PEs with skin lipids and proteins by monitoring shifts in characteristic vibrational bands(Ramzan et al., 2022; Zhang et al., 2023b). Complementarily, X-ray scattering techniques provide critical structural insights into the SC lipid matrix. Small-angle X-ray scattering (SAXS) probes the lamellar organization, including the disordering of the long and short periodicity phases (LPP and SPP)(Horita et al., 2015; Jia et al., 2024); while wide-angle X-ray scattering (WAXS) characterizes alterations in the lateral packing of lipid hydrocarbon chains and their phase transitions (e.g., from orthorhombic to hexagonal)(Moghadam et al., 2013).

This review, therefore, underscores a comprehensive and integrated approach. We systematically dissect PEs across key dimensions: from their diverse molecular mechanisms and structural classifications to the advanced characterization techniques that decipher these interactions at an atomic scale. Furthermore, this exploration extends to the practical application dimension, evaluating the performance of PEs across various dosage forms and their translation into successful clinical products. This multifaceted analysis aims to bridge the gap between fundamental research and formulation development, providing a reference for the rational design of next-generation transdermal delivery systems.

2. Skin

As the largest organ of the human body, the skin functions both as a protective barrier and as the primary interface for TDDS. The SC serves as the main obstacle to drug permeation, owing to its tightly packed, keratinized corneocytes embedded within intercellular lipid lamellae. This highly organized “brick-and-mortar” architecture, comprising dense keratin filaments and lamellar lipid bilayers, creates a hydrophobic matrix that restricts the diffusion of hydrophilic molecules. However, skin appendages such as hair follicles and sweat glands provide alternative, low-resistance pathways for drug transport(Chopra and Gupta, 2022). Fig. 1 depicts the anatomical structure of the skin and the principal permeation routes across the SC.

Fig. 1.

The schematic diagram of the skin structure and the penetration pathways of drugs through the SC barrier.

2.1. Epidermis

The epidermis is organized into four principal layers, arranged from the innermost to the outermost: the stratum basale, stratum spinosum, stratum granulosum, and SC. In thick, glabrous skin, such as that of the palms and soles, a fifth layer, the stratum lucidum, lies between the stratum granulosum and the SC, providing additional protection against mechanical shear. The stratum basale contains keratinocytes, melanocytes, and other specialized cell types. Through a process of terminal differentiation, keratinocytes progressively transform into anucleate corneocytes within the SC, where, together with intercellular lipids such as ceramides, they form the epidermal barrier that minimizes transepidermal water loss and shields against environmental insults(Vávrová et al., 2017). The stratum granulosum supports barrier integrity through the secretion of lamellar bodies and the production of terminal differentiation proteins(Chen et al., 2024a). This stratified architecture is essential for skin homeostasis and represents a critical target for topical drug delivery and dermatological interventions.

2.2. SC and its lipids

The SC features a distinctive “brick-and-mortar” architecture, consisting of corneocytes embedded within an intercellular lipid matrix. This structural arrangement imposes strict limitations on the permeation of molecules, particularly those with molecular weights exceeding 500 Da or partition coefficients (log P) outside the optimal range of 1 to 4(Mishra et al., 2019). Furthermore, the ionization state (pKa) of a drug and the formulation pH determine the ratio of uncharged (more permeable) to charged species, directly impacting its diffusion efficiency across the lipophilic SC barrier(Oakley and Swarbrick, 1987). Permeation can be hindered by high hydrogen-bonding capacity (HBD + HBA) and molecular flexibility (a high number of rotatable bonds). Furthermore, high thermodynamic activity in the vehicle enhances diffusivity by increasing the driving force (Reyes et al., 2023). The keratin filament network within corneocytes provides mechanical strength to the SC, while the LPP of the intercellular lipids regulates its selective permeability. SC lipids, primarily ceramides, cholesterol, and free fatty acids, are essential for maintaining the stability of the lamellar organization, which comprises both LPP and SPP structures(Mojumdar et al., 2015; Uche et al., 2021). It is important to note that interspecies differences in SC thickness and lipid composition among common animal models, such as human, porcine, and murine skin, significantly impact the interpretation of in vitro permeation data(Praça et al., 2018). These variations are summarized in Table 1.

Table 1.

Comparative analysis of SC thickness and lipid composition profiles across different animal models.

Characterized animal models	SC thickness (μm)	Principal lipid constituents	Proportion of lipid components	References
Human	12.5–18.2	Cholesterol esters, free fatty acids, cholesterol, and ceramides	15:16:32:37	(Bohling et al., 2014; Norlen et al., 1999; Todo, 2017; van Smeden and Bouwstra, 2016) (Jung and Maibach, 2015)
Pig	9.1–26.4	Ceramides, cholesterol, and free fatty acids(accounting for 95 % of total lipids)	Exhibiting high similarity to human skin and frequently employed as surrogate models for human skin evaluation	(Gray et al., 1982; Jung and Maibach, 2015; Krumpholz et al., 2022; Mahrhauser et al., 2015; Todo, 2017)
Rat	15.4–18	Ceramides, cholesterol, and free fatty acids	45–50:25:10–15	(Jung and Maibach, 2015; Todo, 2017)
Rabbit	11.7	Ceramide, cholesterol, cholesterol esters, and triglycerides	35:11:32:5	(Jung and Maibach, 2015)
Dog	1.9–3.6	Ceramides, cholesterol, and free fatty acids	Ceramide profiles demonstrate elevated levels of EOS, NS/NdS, and AS/NH species.	(Chermprapai et al., 2018; Inman et al., 2001)

The evaluation of transdermal PEs requires appropriate skin models due to critical interspecies differences in SC structure. Human skin remains the gold standard, sourced from ethical donors (trunk/thigh), dermatomed to 250 ± 50 μm, with barrier integrity confirmed by TEWL (≤ 15 g/m²/h)(FDA Guidance document, 2022). Porcine ear skin, obtained from 6 to 8-week-old Yorkshire weanlings, serves as an optimal surrogate. It is typically prepared to include the full epidermis and partial dermis; its correlation with human skin reaches R² = 0.88 for lipophilic PEs with lower variability (21 %)(Barbero and Frasch, 2009; Riviere et al., 1986; Simon and Maibach, 2000). Both male Wistar rats (200 ± 20 g)(Liu et al., 2025) and 15-week-old male SKH-1 hairless mice(Eros et al., 2012) can be utilized as skin models in TDDS experiments.

2.3. Dermis

The dermis, located beneath the epidermis, consists predominantly of connective tissue rich in collagen and elastin fibers, as well as an extensive network of blood vessels and nerves, which together provide essential structural support to the overlying epidermis. Acting primarily as a hydrophilic environment, the dermis generally offers minimal resistance to the permeation of most substances, although it can present a barrier to highly lipophilic compounds(Kováčik et al., 2020). The dermis is pivotal for transdermal delivery, functioning both as a systemic absorption gateway via its vasculature(Nogueira et al., 2022) and as a drug reservoir via extracellular matrix binding, especially for lipophilic compounds(He et al., 2005). Enhancing dermal drug deposition is therefore critical, as demonstrated by PEs like oleic acid-ethanol elevating S-Methyl-L-Methionine retention(Kim et al., 2017), or copaiba oil increasing ibuprofen distribution for localized efficacy(Nogueira et al., 2022). The efficacy of transdermal prodrug delivery is dependent on their hydrolysis by dermal metabolizing enzymes, such as carboxylesterase, to liberate the active parent drug. For instance, caproyl-propranolol is hydrolyzed during skin penetration, leading to the liberation of active propranolol for delivery(Imai et al., 2013).

3. Different transdermal delivery dosage forms and their mechanisms of action

3.1. Creams and patches

Conventional transdermal formulations, such as creams and patches, primarily rely on passive diffusion for drug delivery. However, their therapeutic effectiveness is significantly limited for compounds with molecular weights above 500 Da or those exhibiting high hydrophilicity(Anjali and Sanchit, 2024; Kováčik et al., 2020). Cream bases facilitate uniform drug dispersion and improve permeation by increasing the contact area between the drug and the skin surface. Transdermal patches enable controlled drug release through diffusion from an adhesive matrix, followed by permeation across the skin barrier into systemic circulation, sustaining plasma drug concentrations over time(Yerra et al., 2023). Transdermal patches are primarily categorized into three systems. The first is the reservoir patch, which utilizes a controlled-release membrane (e.g., scopolamine patch) (Fig. 2A). The second is the matrix patch, where drugs are embedded in polymer matrices. These can be conventional forms with declining release rates (e.g., nicotine patch), or advanced versions that enable sustained delivery for up to 7 days (e.g., fentanyl patch) (Fig. 2B-C). The third and most predominant is the drug-in-adhesive system, which integrates medication directly into the pressure-sensitive adhesives (PSA) (e.g., nitroglycerin patch - NitroDur II®) (Fig. 2D)(Pastore et al., 2015).

Fig. 2.

Schematic diagram of different dosage forms for transdermal drug delivery systems. (A-D) Different types of patches; (E) Liposome; (F) Polymeric micelle; (G) Solid Lipid nanoparticle; (H) Nanoemulsion; (I-M) Different types of MNs; (N) Iontophoresis-driven porous microneedles; (O) Ultrasound-mediated delivery.

PEs incorporated into creams and patches improve transdermal drug delivery by disrupting the lipid organization of the SC(Jiang et al., 2024; Li and Chantasart, 2019). For example, the addition of 6 % isopropyl myristate (IPM) to a hydrocortisone cream significantly increased drug diffusion through the SC and increased the drug's partition coefficient, resulting in approximately a 2.77-fold increase in steady-state flux compared to the base formulation(Simoes et al., 2020). Similarly, inclusion of 5 % allantoin in ibuprofen patches improved percutaneous permeability by about 2.8-fold relative to formulations without PEs(Bednarczyk et al., 2023).

3.2. Hydrogels

Hydrogels, characterized by their three-dimensional cross-linked hydrophilic polymer networks, offer high biocompatibility, effective skin adhesion, and controlled drug release. By improving skin hydration and prolonging drug-skin contact, hydrogels create an ideal microenvironment for the action of PEs(Bashyal et al., 2020). Similarly, Transcutol® P and propylene glycol enhanced skin retention of glabridin and licochalcone A in Carbomer 940 hydrogel, with enhancement ratios of 1.14 and 1.82 respectively, by disrupting drug-polymer interactions and SC lipids(Wang et al., 2022a, Wang et al., 2022b). Incorporation of polyoxyethylene 2-oleyl ether enhanced the transdermal permeation of procaine from HPMC-poloxamer 407 hydrogel by 1.77-fold compared to the enhancer-free formulation(de Araújo et al., 2013).

3.3. Nanopharmaceutical formulation

Nanocarrier systems include a diverse range of formulations such as liposomes (Fig. 2E), polymeric micelles (Fig. 2F), solid lipid nanoparticles (Fig. 2G), and nanoemulsions (Fig. 2H)(Boucetta et al., 2024; Diogo et al., 2023). For instance, a chitosan-modified nanoemulsion demonstrated increased transdermal delivery of lornoxicam, increasing steady-state flux across the skin by approximately 1.12-fold(Khan et al., 2022). Nanocarriers facilitate transdermal drug penetration by improving solubility and stability, increasing skin hydration, and enabling enhanced permeability via appendageal pathways such as hair follicles.

Penetration enhancer-containing vesicles (PEVs) incorporating Labrasol® (caprylocaproyl polyoxyl-8 glycerides) as a PE represent a class of highly skin-permeable elastic vesicles. Their enhanced membrane deformability facilitates penetration through the SC, overcoming the aggregation and permeation challenges associated with conventional liposomes. Minoxidil-loaded Labrasol®-PEVs achieved a SC drug accumulation of 11.07 ± 0.77 %, which is 2.75-fold higher than that of conventional liposomes (4.02 ± 0.15 %). FTIR analysis confirmed the homogeneous distribution of PEVs within the SC and revealed characteristic minoxidil absorption peaks in skin samples, demonstrating their penetration-enhancing efficacy(Mura et al., 2013).

Nanocrystals enhance transdermal delivery by reducing drug particle size to 100–700 nm, increasing saturation solubility and creating a high concentration gradient on skin surface(Li et al., 2018). This operates through dual pathways: transepidermal permeation driven by concentration gradient, and follicular deposition forming sustained-release reservoirs(Li et al., 2018; Xiang et al., 2023). Pramipexole nanocrystals demonstrated 2.75-fold higher permeation than coarse suspension, with 34 % via follicular route(Li et al., 2018). Particle size dictates pathway selection: 60 nm curcumin nanocrystals favored epidermal penetration while 480 nm particles accumulated in follicles(Xiang et al., 2023). Cellulose nanocrystals achieved 79.3 % hydroquinone loading with sustained release(Taheri and Mohammadi, 2015). Nucleic acid-based nanostructures provide a programmable platform for transdermal drug delivery. A 17-nm DNA tetrahedron penetrated mouse skin and improved doxorubicin delivery to melanoma(Wiraja et al., 2019). Microneedle-delivered, extracellular vesicle-encapsulated mRNA enhanced collagen I production in photoaged mouse skin(Nimrawi et al., 2025). Iontophoresis of a CYP3A2-targeting ASO increased midazolam-induced sleep duration by 165 %(Brand et al., 2001). A 20.4 kDa IL-23 RNA aptamer in a cream penetrated intact human skin, achieving therapeutic levels in epidermis and dermis(Lenn et al., 2018).

3.4. Physical methods

Physical enhancement strategies employ various techniques to transiently disrupt the SC and facilitate drug permeation. Microneedles (MNs) mechanically create 50–200 μm microchannels that bypass the SC lipid barrier. MNs comprise five structural classes. Solid MNs create microchannels simply and cost-effectively (Fig. 2I). Dissolving MNs have limited drug-loading capacity (Fig. 2J). Hollow MNs allow high-dose infusion but have mechanical limits (Fig. 2K). Hydrogel MNs provide sustained delivery but require reinforcement (Fig. 2L). Coated MNs enable rapid release but have minimal capacity (Fig. 2M)(Moawad et al., 2025). This approach has proven effective for diverse therapeutics: polymer-based MNs sustained stable blood glucose levels with metformin over multiple treatments(Li et al., 2025). Finasteride-loaded dissolving MNs demonstrated sustained in vitro drug release over 14 days, with extrapolated in vivo release duration of 7 days(Karve et al., 2024).

Iontophoresis utilizes low-intensity electrical currents to drive charged molecules across the skin, enabling non-invasive delivery of a wide range of therapeutics, including local anesthetics and anti-inflammatory agents(Akimoto et al., 2014). The iontophoresis-driven porous MNs system potentiates allopurinol delivery—achieving 1.54 mg delivered at 1.5 V in 30 min via combined microchannels and electrokinetic force(Wang et al., 2025b) (Fig. 2N). Electroporation applies short, high-voltage electrical pulses to transiently permeabilize the SC, demonstrating high efficacy and low toxicity; however, its application is predominantly limited to hydrophilic drugs due to the hydrophilic nature of the pores generated and the inherent permeability constraints of the SC(Jia et al., 2005). Sonophoresis significantly enhances the transdermal permeability of RNA therapeutics by utilizing ultrasound-induced cavitation to create transient aqueous microchannels within the SC, thereby facilitating efficient intradermal and systemic delivery(Nimrawi et al., 2025) (Fig. 2O).

Smart transdermal systems combine MNs and iontophoresis to create programmable microchannels for precision drug release. This closed-loop platform addresses traditional limitations in drug loading and passive permeation(Lee et al., 2018). A conductive hydrogel-based smart wearable MN device integrated with iontophoresis achieved a lidocaine delivery efficiency of 96.3 ± 6.4 % at a current density of 3 mA/cm² for painless dental anesthesia(Wang et al., 2025a). In a proof-of-concept study for glycemic management, glucose-responsive MN patches achieved closed-loop blood glucose regulation in diabetic minipigs (> 25 kg), maintaining normoglycemia for over 20 h with a minimal patch size of 5 cm², thereby highlighting their considerable clinical potential(Yu et al., 2020).

4. Classification of PEs

PEs serve as critical functional agents in optimizing transdermal drug delivery by reversibly modulating the skin barrier or altering the physicochemical properties of drugs to facilitate permeation(Kováčik et al., 2020). Research between 2000 and 2015 predominantly concentrated on conventional chemical PEs, such as alcohols and fatty acid esters. Since 2016, however, there has been a marked shift towards exploring novel PEs, including peptide-based compounds and ionic liquid formulations(Sidat et al., 2019; Zhang et al., 2022). The classification of PEs can be systematically approached from three dimensions: origin, physicochemical properties, and structural characteristics.

Regarding origin, natural PEs, such as terpenes(Lim et al., 2009; Schafer et al., 2023), essential oils(Alhasso et al., 2022), and skin-penetrating peptides(Kumar et al., 2015), offer advantages in biocompatibility and exhibit specific molecular interactions with skin components. Synthetic PEs, including ionic liquids(Gao et al., 2024; Sidat et al., 2019) and block copolymers(Saitani et al., 2024), contribute to precision drug delivery owing to their tunable molecular architectures and well-defined physicochemical profiles. From a physicochemical perspective, surfactant-based PEs regulate interfacial properties through their hydrophilic-lipophilic balance, with significant functional differences between nonionic and anionic subclasses(Shivani and Puri, 2021). Solvent-type enhancers, such as alcohols and sulfoxides, primarily act by modifying drug solubility and altering the microenvironment of the SC(Dragicevic et al., 2015). Structurally, the diversity of PEs is further reflected in linear or branched polymeric materials and supramolecular assemblies driven by molecular recognition mechanisms. These classification dimensions are interrelated and complementary, offering multidimensional insight into penetration enhancement mechanisms. Building on this framework, the present study emphasizes the investigation of characteristic functional groups to further elucidate PE diversity. The classification scheme is depicted in Fig. 3.

Fig. 3.

Classification of PEs.

4.1. Fatty acids and their esters

Long-chain fatty acids and their esters, such as linoleic acid, docosahexaenoic acid, oleic acid, and linolenic acid, improve transdermal drug permeation primarily through interactions with SC lipids. Their pronounced lipophilicity facilitates integration into the lipid bilayer, where they intercalate with endogenous lipids, modulating crystallinity and fluidity. This disruption increases membrane fluidity, promoting drug diffusion. Oleic acid, in particular, has demonstrated significant permeation-enhancing effects(Wong and Khaizan, 2012). For example, sulfanilamide films containing oleic acid achieved approximately a three-fold increase in 24 h percutaneous permeation compared to PE-free films (38.69 % vs. 22.18 %). Similarly, an oleic acid–reinforced PEGylated polymethacrylate transdermal film for atorvastatin delivery produced an 8.6-fold increase in area under the curve (AUC) over PEG/oleic acid-free films, and a 2.8-fold increase relative to oral administration(El-Say et al., 2021). In ibuprofen patches, incorporation of 5 % oleic acid resulted in a cumulative 24 h permeability of 163.31 ± 24.42 μg/cm², approximately 2.8 times higher than control patches, suggesting that its mechanism of action involves disruption of the SC lipid barrier(Bednarczyk et al., 2023).

4.2. Azone derivatives

Azone derivatives, including laurocapram(Li and Chantasart, 2019; Wang et al., 2024) and 1-dodecylhexahydro-2H-azepin-2-one(Evrard et al., 2001), belong to nitrogen-containing heterocyclic compounds whose penetration-enhancing mechanisms are governed by alkyl chain length (C8-C16)-dependent lipid bilayer perturbation. The primary advantage of these compounds lies in their capacity to disrupt the tight packing and ordered arrangement of lipid bilayers, facilitating drug permeation. The hydrogel formulation containing 0.75 % azone demonstrated a steady-state flux of 1604.10 ± 102.83 μg·cm⁻²·h⁻¹ for levamisole hydrochloride, whereas the azone-free formulation exhibited a significantly lower flux of 550.02 ± 260.79 μg·cm⁻²·h⁻¹, representing a 2.92-fold enhancement in transdermal permeation(Chen et al., 2018).

4.3. Terpenes

Terpenes are lipophilic compounds that improve transdermal drug delivery primarily by disrupting the structural organization of SC lipids(Schafer et al., 2023; Balmanno et al., 2024). Common examples include eucalyptol, limonene(Yousef et al., 2019), menthol(Wang and Meng, 2017), menthone, anethole, eugenol(Ahad et al., 2016), β-caryophyllene, perilla ketone(Zhao et al., 2025), and nerolidol(Chan et al., 2016). Menthone has been reported to significantly increase the permeation of various bioactive compounds, including osthole, ligustrazine, ferulic acid, puerarin, and geniposide, by perturbing the lamellar packing of SC lipids, yielding enhancement ratios of 5.82, 8.54, 20.42, 293.80, and 31.60, respectively(Lan et al., 2016). Likewise, menthol has demonstrated significant permeation-promoting effects, increasing the transdermal flux of sumatriptan succinate, voriconazole, and pantoprazole sodium by approximately 2.49-, 2.25-, and 4.96-fold, respectively(Yadav et al., 2025).

4.4. Alcohols and alkanols

Alcohols and alkanols, a class of hydroxyl-containing PEs, include agents such as ethanol(Limpongsa et al., 2015), propylene glycol(Carrer et al., 2020), and benzyl alcohol(Nanayakkara et al., 2005). Their permeation-enhancing activity is primarily attributed to their ability to intercalate into the SC lipid matrix, disrupting its ordered arrangement and reducing the skin's barrier resistance. For example, 1-octanol has been shown to increase the transdermal permeation of corticosterone by approximately 10-fold(Chantasart and Li, 2012). Similarly, propylene glycol, as the principal component of a glycolic extract–loaded nanostructured lipid carrier, has demonstrated a roughly two-fold enhancement in the transdermal release and deep skin penetration of asiaticoside(da Rocha et al., 2019).

4.5. Amino acids and their derivatives

This category encompasses PEs derived from or based on the structure of amino acids, including their amide and ester derivatives. Amide-based PEs are characterized by the presence of amide functional groups and include compounds such as N,O-diacyl-L-alaninol(Sivaramakrishna et al., 2021), and L-Pro2(Janusová et al., 2013). The L-Pro2 ester has been reported to increase the transdermal flux of theophylline by 40-fold when formulated in 60 % propylene glycol(Janusová et al., 2013). Similarly, n-dodecyl-N-acetylprolinate has demonstrated a 34.3-fold enhancement in the permeability coefficient for hydrocortisone(Ghafourian et al., 2004).

4.6. Sulfoxides

Sulfoxide-based PEs, exemplified by dimethyl sulfoxide (DMSO), contain sulfoxide functional groups and facilitate transdermal drug delivery through multiple mechanisms. These include disruption of intercellular lipid organization within the SC, modification of keratin secondary structure, and enhancement of drug partitioning due to their strong solvating capacity(Williams and Barry, 2004). For instance, a formulation containing 15 % (w/w) DMSO achieved an optimal 2.2-fold increase in the permeation of diclofenac diethylamine(Ali et al., 2015). Similarly, a hydrogel incorporating 5 % (w/w) DMSO, 6 % (w/w) gabapentin, and 0.75 % (w/w) Carbopol® significantly increased gabapentin penetration through human skin, yielding an apparent flux of 7.56 ± 5.50 μg/cm²/h(Martin et al., 2017).

4.7. Peptides

Peptide-based PEs are short-chain biomolecules composed of 2–50 amino acids linked via amide bonds, with examples including SPACE peptide(Chen et al., 2014; Hsu and Mitragotri, 2011), TD-1(Chen et al., 2006), and poly-arginine(Candan et al., 2012). Notably, SPACE, TD-1, poly-arginine, and the HIV-1 TAT-derived peptide discussed below, all belong to the category of cell-penetrating peptides. The SPACE peptide has been shown to significantly improve the dermal delivery of chrysomycin A, increasing its cutaneous concentration by approximately threefold compared to the free drug(Cai et al., 2025). Furthermore, conjugation of the HIV-1 TAT-derived peptide with the Glycine–Lysine–Histidine sequence resulted in a 36-fold increase in transdermal permeation efficiency relative to Glycine–Lysine–Histidine alone, substantially improving skin penetration(Muhammad et al., 2025).

4.8. Ionic liquid

Ionic liquid-based PEs are characterized by low toxicity, high chemical stability, and tunable physicochemical properties, rendering them highly effective for improving transdermal drug delivery(Dobler et al., 2013). Representative examples include choline–geranic acid ionic liquids(Banerjee et al., 2017; Chen et al., 2024b), 1,4-diazabicyclo[2.2.2]octane derivatives(Monti et al., 2017), and imidazolium-based ionic liquids(Zhang et al., 2017). Their enhancement mechanisms primarily involve disruption of SC lipid organization and modulation of the skin's solubility parameters to favor drug permeation. Choline–geranic acid ionic liquids, particularly at 1:2 and 1:4 M ratios, have demonstrated pronounced facilitation of insulin penetration through the skin. Similarly, a diethylamine–ketoprofen drug–ionic liquid conjugate yielded a 7.32-fold increase in transdermal flux.

4.9. Surfactant

Surfactant-based PEs are amphiphilic molecules comprising a hydrophilic head group and a hydrophobic tail, enabling them to reduce surface tension and interact with skin lipid domains(Shafiei et al., 2023). Examples include Tween 80(Khan et al., 2016), polyglyceryl-3 dioleate (POCC) (Sun et al., 2023), C18-OPK, and C12-OPK(Abruzzo et al., 2017). Among these, POCC has been shown to increase the transdermal delivery of tofacitinib, achieving a skin penetration level of 29.33 ± 3.47 μg/cm²(Song et al., 2022).

4.10. Polysaccharides

Polysaccharides serve as biocompatible skin PEs. Chitosan derivatives disrupt SC lipids and enhance skin hydration to improve drug permeation(Ma et al., 2022). Fucoidan forms alginate-based hydrogels that promote calcein permeation(Barbosa et al., 2023). Hyaluronic acid enhances skin hydration, disrupts the tight structure of the SC, and interacts with keratin and lipids in the SC, altering their conformation and arrangement(Ni et al., 2023).

5. Mechanism of action of PEs

PEs promote drug delivery by reversibly reducing the barrier resistance of the SC. A thorough understanding of their underlying mechanisms is essential for the rational design of potent enhancers and the judicious selection of excipients in transdermal formulations. Fig. 4 illustrates the principal mechanisms by which PEs facilitate skin permeation.

Fig. 4.

The penetration mechanism of PEs.

5.1. Disruption of SC lipid bilayer structure

Disruption of the SC lipid bilayer involves the intercalation of PEs into the lipid matrix, leading to alterations in bilayer architecture, increased lipid fluidity, and in some cases, the formation of transient aqueous channels. These modifications facilitate enhanced drug permeation. Representative PEs employing this mechanism include fatty acids and their esters, azone derivatives(Evrard et al., 2001), terpenes(Schafer et al., 2023), alcohols and alkanols(Limpongsa et al., 2015), as well as amide-based compounds(Janusová et al., 2013). For example, borneol has been shown to increase the permeation of 5-fluorouracil, antipyrine, aspirin, salicylic acid, and ibuprofen by 10.57-, 32.84-, 19.81-, 12.76-, and 9.78-fold, respectively, through disruption of SC lipid organization(Yi et al., 2016).

5.2. Interaction with keratin proteins

PEs facilitate transdermal drug delivery by interacting with keratin proteins within the SC, inducing conformational modifications or altering their hydration state. These interactions increase SC porosity, promoting drug diffusion. Representative PEs employing this mechanism include sulfoxide derivatives (Shabbir et al., 2016)and peptide-based enhancers(Kumar et al., 2015). For instance, urea has been reported to increase caffeine permeation by approximately 50 % through keratin interaction–mediated conformational changes(Schafer et al., 2023).

5.3. Enhance drug partitioning into the SC

PEs can modulate the partition coefficient between the formulation vehicle and the SC, promoting drug release from the formulation and improving subsequent partitioning into the skin barrier(Wennberg et al., 2023). This mechanism is particularly prominent with alcohol-based enhancers(Carrer et al., 2020).

5.4. Lipid extraction

One well-recognized strategy by which PEs improve transdermal delivery involves the depletion and reorganization of SC lipids. By selectively extracting lipid components, modifying their conformational order, and inducing phase separation, PEs compromise the structural integrity of the lipid matrix, generating pathways for drug diffusion(Lim et al., 2009). This mechanism has been demonstrated with various chemical classes, including terpenes(Lan et al., 2016; Vaddi et al., 2003), alcohols(Gupta et al., 2020), and surfactants(Fait et al., 2018). For example, clove oil produced a 7.91-fold increase in the steady-state flux of mefenamic acid after only 2 h of pretreatment, an effect attributed to its lipid-extraction capacity(Salimi and Sheykholeslami, 2023). Similarly, a lipid-based vesicular system composed of Span 40, soy lecithin, and cholesterol (4.5,4.5,1, w/w) significantly enhanced frusemide penetration, with FT-IR and DSC analyses confirming SC lipid removal as the primary mode of action(Azeem et al., 2009).

5.5. Synergistic effect

Another pathway by which PEs exert their effect involves synergistic actions that simultaneously disrupt the lipid organization of the SC and improve drug solubility within the delivery vehicle(Lan et al., 2014). This dual mechanism can amplify permeation efficiency. For instance, a binary co-solvent system comprising ethanol and Transcutol® in equal proportions (pH 7.5) increased the transdermal delivery of diclofenac and piroxicam by approximately 13.1-fold and 39.7-fold, respectively, relative to a PBS control (pH 7.5, 32 °C) lacking PEs(Caserta et al., 2024). Such outcomes highlight the potential of combining lipid-disruptive agents with solubilizers to achieve improved permeation profiles.

6. Penetration enhancement efficacy assessment and advanced characterization technologies for TDDS

6.1. Fourier-transform infrared spectroscopy

FTIR is a powerful analytical tool for probing molecular-level alterations in the SC induced by PEs. Such modifications are detected through shifts in characteristic absorption bands, enabling assessment of both lipid and protein structural changes(Ramzan et al., 2022). Perturbations in keratin secondary structure are reflected in variations of the amide I/II bands, whereas disruptions in lipid packing are revealed within the C—H stretching region(Wang et al., 2022a, Wang et al., 2022b). The magnitude of the v_as CH₂ band shift near 2920 cm⁻¹ correlates positively with the extent of ceramide structural disorder, serving as a sensitive marker of barrier impairment(Zhang et al., 2023b). For example, Span 80 surfactants have been shown to induce lipid bilayer perturbations, evidenced by blue shifts in v_as CH₂ (2918 → 2923 cm⁻¹) and v_s CH₂ (2850 → 2852.3 cm⁻¹) vibrations(Li et al., 2017).

6.2. Nuclear magnetic resonance studies

NMR spectroscopy provides molecular-level insight into structural organization and dynamic behavior by monitoring nuclear spin transitions in a magnetic field(Perrone et al., 2024). In skin research, solid-state NMR has proven particularly valuable for characterizing PE-induced alterations in SC lipid and protein dynamics(Pham et al., 2021). For instance, incorporation of 20 wt% butylene glycol was found to diminish the characteristic solid lipid resonance at 33.4 ppm while enhancing the liquid lipid signal at 31 ppm, indicating increased lipid fluidity. This transition from ordered to more mobile lipid states correlates with improved transdermal delivery, as evidenced by enhanced cutaneous permeation of lidocaine hydrochloride(Kis et al., 2022).

6.3. Small-angle X-ray scattering experiment

SAXS investigations have shown that PEs modulate skin barrier function by altering the supramolecular organization of SC lipids. Disruption of the long periodicity phase (LPP) manifests as a decline in its diffraction peak intensity, often accompanied by a structural rearrangement from lamellar sheets to vesicular assemblies, changes consistent with increased lipid fluidity and higher drug permeability. The short periodicity phase (SPP) is particularly sensitive to certain PEs, with its repeat distance shrinking from 6.97 nm to complete loss in some cases, reflecting pronounced lamellar disorder. For example, in an ethanol/water (60,40 v/v) mixture, the SPP spacing decreases from 6.29 nm to 5.86 nm, while the LPP (∼13 nm) and hydrocarbon chain packing remain essentially intact, indicating selective SPP perturbation(Horita et al., 2015). Incorporation of POCC shifts the LPP spacing from 13.69 nm to 13.11 nm without significantly affecting the SPP, revealing that POCC primarily targets LPP architecture(Jia et al., 2024). These phase-specific alterations highlight distinct enhancer–lipid interactions and provide mechanistic evidence linking SC nanostructural destabilization to improved transdermal drug delivery.

6.4. Neutron diffraction

Neutron diffraction offers exceptional sensitivity to light atoms, particularly hydrogen and deuterium, owing to the strong interaction of neutrons with atomic nuclei(Schroeter et al., 2013). When coupled with selective deuterium labeling, this technique provides high-resolution mapping of water and lipid distributions in the SC, allowing direct assessment of PE-induced changes in hydration and lipid architecture. Using this approach, studies have shown that IPM disrupts SC lipid lamellae by eliminating the LPP and consolidating the structure into a single SPP with a repeat distance of 48.4 Å(Eichner et al., 2017). Such alterations underscore the ability of certain PEs to selectively destabilize lipid phases, therefore facilitating transdermal permeation.

6.5. Differential scanning calorimetry experiment

DSC probes thermal transitions in skin lipids by tracking heat flow during controlled temperature changes, offering direct insight into PE-induced modifications of lipid packing(Ramzan et al., 2022). Shifts in phase transition temperature (T_m), reductions in enthalpy, or disappearance of characteristic peaks signify increased lipid fluidity and disrupted lamellar order(Ramzan et al., 2022). Interspecies differences in baseline lipid phase behavior account for variability in enhancer effects(Kocsis et al., 2022). For example, L-menthol promotes S-flurbiprofen permeation by lowering the SC glass transition temperature (T_g) from 65 °C to 58 °C, weakening lamellar stability(Zhang et al., 2023b). Similarly, azone decreases the SC lipid T_m by ∼6.2 °C, facilitating improved drug diffusion across the barrier(Ibrahim and Li, 2010).

6.6. Raman studies

Raman spectroscopy enables molecular-level assessment of PE effects on the SC by tracking characteristic amide and C—H stretching vibrations(Wu et al., 2023). Quantitative analysis of lipid chain order, using the v_asCH₂/v_sCH₂ peak area ratio, shows that POCC reduces this value from 2.10 to 1.54, indicating disruption of lipid packing and increased barrier fluidity(Sun et al., 2023). Confocal Raman microscopy extends this capability to three-dimensional mapping of drug and enhancer localization within skin, revealing an inverse relationship between POCC and lauric acid–tofacitinib levels. Such spatially resolved data illuminate synergistic interactions between ion pairs and PEs in enhancing transdermal drug delivery(Song et al., 2022).

6.7. Confocal laser scanning microscopy

CLSM provides high-resolution, non-invasive optical sectioning, enabling three-dimensional visualization of thick skin samples with minimal preparation(Bayguinov et al., 2018). This technique allows direct measurement of PE-mediated penetration depth for fluorescent probes within the SC(Sharif et al., 2020). For example, incorporation of 10 % Span increased Nile red penetration from 8 μm to 16 μm(Li et al., 2017), while 10 % POCC enhanced FITC penetration from 10 μm to 25 μm(Jia et al., 2024).

6.8. Wide-angle X-ray scattering

WAXS measures X-ray scattering at wider angles and provides critical information about the lateral packing arrangements of lipids in the SC, such as orthorhombic, hexagonal, and liquid phases(Bouwstra and Ponec, 2006). This technique is particularly valuable for quantifying the disordering effects of PEs on the SC's lipid barrier by detecting phase transitions from the tight orthorhombic packing to more permeable hexagonal or liquid states(Cornwell et al., 1994). In a comprehensive study investigating various PEs, Moghadam et al. utilized WAXS to directly correlate structural changes with enhancement efficacy(Moghadam et al., 2013). For example, they found that treatment with the ionic surfactant sodium dodecyl sulfate resulted in the complete disappearance of the characteristic orthorhombic peaks, indicating a total disruption of the dense lipid packing. Conversely, the terpene Nerol induced a significant reduction in orthorhombic peak intensity and a decrease in the peak height ratio, suggesting a transition towards a more disordered hexagonal phase(Moghadam et al., 2013).

Spectroscopic, thermodynamic, and imaging approaches together deliver a comprehensive mechanistic understanding of chemical enhancer action, forming a robust characterization platform for the rational design and optimization of transdermal delivery systems. Representative examples are shown in Fig. 5.

Fig. 5.

Schematic representation of characterization techniques: (A) FTIR spectroscopy(Li et al., 2017), (B) ¹³C NMR(Kis et al., 2022), (C) SAXS(Jia et al., 2024), (D) Neutron diffraction(Eichner et al., 2017), (E) DSC(Ibrahim and Li, 2010), (F) Raman spectroscopy(Sun et al., 2023), (G) Confocal Raman imaging(Song et al., 2022), (H) CLSM(Jia et al., 2024), and (I) WAXS(Moghadam et al., 2013).

7. Emerging computational approaches for PE screening and mechanism study

7.1. Quantitative structure-activity relationship (QSAR)

QSAR establishes mathematical models between the chemical descriptors (e.g., log P, molecular weight, topological indices) of PEs and their enhancement activity, revealing structure-activity relationships and providing a theoretical tool for the rational design and virtual screening of highly effective enhancers(Ghafourian et al., 2004). Studies indicate that the enhancement mechanism is drug-specific: for polar drugs such as 5-fluorouracil, enhancer activity correlates with electronic properties like hydrogen bond acceptance, whereas for hydrophobic drugs like hydrocortisone, it positively correlates with enhancer log P(Ghafourian et al., 2004; Iyer et al., 2007). Furthermore, QSAR models developed for specific carrier systems (e.g., Poloxamer 407) can effectively predict the transdermal enhancement behavior of various drugs, thereby extending their applicability in pharmaceutical formulation development(Parveen et al., 2025).

7.2. Molecular docking

Molecular docking enables the visualization and quantification of intermolecular interactions at the atomic level, including binding conformations, bonding distances, and binding affinities, thereby facilitating mechanistic studies in TDDS(Zhang et al., 2023b). This technique elucidates complex interactions between formulation components—such as drugs, PEs, and PSA—and skin barrier constituents. For instance, in the design of a dexmedetomidine long-acting patch, molecular docking revealed that the hydrogen-bond distance between the Dex-NA ion pair and the adhesive (2.740 Å) was shorter than that of the free drug Dex (2.848 Å), confirming at the molecular level that the ion-pair strategy enhances drug-adhesive interactions to achieve controlled release(Sun et al., 2023). In a riluzole transdermal patch study, it was demonstrated that the polyglyceryl-3 dioleate enhances drug release and skin permeation by competing for PSA binding sites and weakening drug-polymer interactions(Liu et al., 2025).

7.3. Molecular dynamics simulations and hydrogen bonding analysis

Molecular dynamics simulations reveal the atomic-scale interactions between PEs and SC lipids. Cholesterol incorporation fluidizes lipid bilayers by reducing chain order and promoting gauche conformers(Höltje et al., 2001). Ethanol preferentially extracts free fatty acids through hydrogen bonding and creates trans-bilayer hydrophilic channels at higher concentrations, facilitating drug permeation(Gupta et al., 2020). These findings visually demonstrate the “lipid extraction-structural perturbation-channel formation” cascade, providing molecular-level insights into macroscopic permeation enhancement observed by FTIR and SAXS. Hydrogen bonding analysis within molecular dynamics simulations quantitatively characterizes competitive interactions between PEs and SC components. This molecular-level investigation elucidates the disruption of skin barrier integrity through competitive hydrogen bonding mechanisms. Key parameters including hydrogen bond energy (e.g., −1.703 kcal/mol) and bond distance (e.g., 2.537 Å) characterize interaction strength, supported by FT-IR spectral shifts(Luo et al., 2020).

8. Applications of PEs in diverse drug delivery systems and commercial products

PEs constitute a diverse class of agents exhibiting multifaceted mechanisms of action. Their selection, concentration, and mode of incorporation are highly dependent on the dosage form, such as patches, creams, or hydrogels, owing to differences in formulation architecture, release kinetics, and target therapeutic profiles.

8.1. Transdermal patch

Transdermal patches offer distinct benefits, specifically the ability to sustain consistent plasma drug levels and improve patient adherence(Güngör et al., 2020). Structurally, most patches comprise three essential components: a backing layer, a drug-loaded reservoir, and a membrane that regulates release(Singh et al., 2024b). Within these systems, PEs may be formulated to diffuse alongside the drug or embedded within the membrane itself, where they modulate skin permeability(Li et al., 2017; Saini et al., 2024).

The effectiveness of a patch depends heavily on fine-tuning the type and concentration of PEs to achieve the desired penetration rate while minimizing irritation potential. For example, incorporating Tween 20 into a pseudoephedrine hydrochloride patch significantly accelerated release, delivering 83.3 % of the drug within 24 h(Samiullah et al., 2020). Likewise, paliperidone patches containing POCC achieved exceptional skin permeation, reaching a cumulative penetration of 98.31 ± 2.79 μg/cm² after 72 h(Xu et al., 2024).

8.2. Creams

As a conventional modality for transdermal drug delivery, creams often exhibit suboptimal permeation performance owing to the formidable barrier function of the SC and potential incompatibilities between the drug and the formulation matrix(Reid et al., 2013). The strategic incorporation of PEs can significantly improve delivery efficiency by modulating SC structure and drug solubility parameters. For instance, oleic acid perturbs the ordered lipid packing within the SC, increasing lipid fluidity and generating transient diffusion channels, facilitating increased delivery of imiquimod from cream-based formulations. IPM similarly acts by disrupting SC lipid organization and increasing membrane fluidity, resulting in a 3.1-fold elevation in hydrocortisone steady-state flux, from 0.31 μg/cm²/h to 0.97 μg/cm²/h, relative to enhancer-free formulations(Simoes et al., 2020). Furthermore, a synergistic system comprising dimethyl isosorbide and ethoxydiglycol (2.5 % each) has been shown to optimize caffeine permeation by simultaneously disrupting SC lipid architecture and increasing drug solubility and thermodynamic activity, yielding a 2.8-fold increase in steady-state flux (from 12.3 μg/cm²/h to 34.6 μg/cm²/h) compared to non-enhanced controls(Reyes et al., 2023).

8.3. Hydrogels

Hydrogels, composed of hydrophilic polymers arranged in a three-dimensional crosslinked network, possess exceptional water absorption capacity and are widely utilized as transdermal drug delivery platforms owing to their biocompatibility, mechanical flexibility, and sustained-release capabilities. These matrices facilitate uniform drug dispersion, enable controlled release, and promote skin retention through their inherent bioadhesive properties(Kim et al., 2023). Despite their ability to accommodate both hydrophilic and hydrophobic therapeutics, the intrinsic permeation-enhancing capacity of hydrogels is generally limited, necessitating the incorporation of PEs to improve transdermal transport. Chitosan derivatives, for example, can augment drug permeation via disruption of SC lipid organization and enhancement of skin hydration(Ma et al., 2022). In the topical delivery of ascorbic acid, an optimized combination of diethylamine with the potent PE L-menthol achieved the highest recorded drug content within the deep skin layers (70.80 ± 14.07 μg/g), highlighting the potential of synergistic enhancer–hydrogel systems in maximizing cutaneous drug deposition(Li et al., 2022). The PEs incorporated in various commercially available dosage forms are systematically summarized in Table 2, with all data sourced from the FDA databases.

Table 2.

Different dosage forms of commercially available drugs and the PEs used.

Dosage form	Trade name	Drug	PEs	Dose/mg	Usage
Patch	Qutenza®	Capsaicin	Diethylene glycol monoethyl ether	179	60-min application of up to four topical systems
	Ztlido®	Lidocaine	Dipropylene glycol	36	No more than 3 patches each time. Use it for 12 h a day and then stop using it for 12 h.
	Salonpas®	Menthol; Methyl Salicylate	Menthol	Menthol 3 %; Methyl Salicylate 10 %	Only one patch can be used each time, and no more than twice a day
	Amlexano®	Amlexanox	Propylene glycol	2	Four times a day
	Oxytrol®	Oxybutynin	Triacetin	36	Apply it twice a week (every 3 to 4 days)
	Neupro®	Rotigotine	Glycerin	1、2、3、4、6、8	Once a day
	Secuado®	Asenapine	Isopropyl palmitate	3.8、5.7、3.8	Once a day
Cream	Acyclovir®	Acyclovir	Propylene Glycol	50	5 times per day
	Terconazole®	Terconazole	Isopropyl Myristate	5	Once a day
	Xerese®	Acyclovir; Hydrocrtisone	Propylene Glycol	Acyclovir 50; Hydrocrtisone 10	5 times per day
	Azelex®	Azwlaic acid	Isopropyl Myristate and Propylene Glycol	200	Twice a day, in the morning and evening
	Topicort®	Desoximetasone	Isopropyl Myristate	0.5、2.5	–
	Zovirax®	Acyclovir	Propylene Glycol	50	Apply 5 times a day for 4 days
	Exelderm®	Sulconazole Nitrate	Propylene glycol and Isopropyl myristate	1 %	Once or twice a day
	Vtama®	Tapinarof	Transcutol®、Propylene glycol, and Polysorbate 80	10	Once a day
	Avage®	Tazarotene	Span® 80	1	Once a day
	Retin-A®	Tretinoin	Isopropyl myristate	20	Once a day
Hydrogel	Lidosite topical system kit®	Epinephrine; Lidocaine Hydrochloride	Glycerin	Epinephrine 1.05; Lidocaine Hydrochloride 100	–

9. Future perspectives and emerging frontiers

Moving beyond current PE strategies, the future of transdermal drug delivery is shifting towards intelligent and personalized systems. Firstly, personalized TDDS will enable precise dosing regimens tailored to individual skin properties, metabolic profiles, and genomic information(Albayati et al., 2025). Secondly, machine learning-based formulation optimization will leverage the analysis of complex composition-structure-activity relationships to virtually screen for optimal drug-PE combinations, drastically reducing development timelines(Yadav et al., 2025). In TDDS formulation, machine learning leverages drug properties and skin permeability data to predict transdermal behavior and optimize formulations. AI aids in selecting PEs by modeling their interaction with the SC, improving penetration and reducing variability. AI-powered simulations further predict drug distribution and release, reducing experimental dependency and advancing personalized transdermal delivery(Albayati et al., 2025). Lastly, the most transformative direction lies in the development of integrated wearable patches with biosensors for feedback-controlled dosing. These systems, combining MNs, sensing elements, and controlled-release modules, can continuously monitor physiological biomarkers (e.g., glucose levels) and dynamically adjust drug administration, achieving true closed-loop theranostics(Wang et al., 2025a). The convergence of these cutting-edge technologies heralds a future where transdermal delivery plays a central role in precision medicine and chronic disease management.

10. Conclusion

PEs represent a cornerstone strategy for addressing the inherent limitations of TDDS. Acting through diverse mechanisms, such as disruption of the SC lipid architecture, modulation of keratin conformation, enhancement of drug partitioning into the SC, and lipid extraction, PEs substantially improve cutaneous drug permeation. Emerging innovations emphasize synergistic integration of advanced materials (e.g., ionic liquids, block copolymers) with physical enhancement modalities (e.g., MNs, electroporation), yielding marked improvements in the bioavailability of complex therapeutics, including peptides, proteins, and vaccines. Future progress will rely on the application of high-resolution in situ analytical techniques, such as confocal Raman spectroscopy, to elucidate molecular-level interactions between PEs, the SC, and co-administered drugs. Such mechanistic insights will underpin the rational design of next-generation enhancers with optimized efficacy–safety profiles. Ultimately, the strategic convergence of PEs with innovative transdermal platforms offers substantial potential to expand the therapeutic landscape, enabling the non-invasive, patient-friendly delivery of biologics, vaccines, and other challenging molecules.

CRediT authorship contribution statement

Yanan Liu: Writing – original draft, Investigation. Man Li: Writing – original draft, Investigation. Daoxuan Xie: Writing – original draft. Guixue Chen: Writing – original draft. Nanxi Zhao: Writing – review & editing, Supervision. Zheng Luo: Writing – review & editing, Supervision, Project administration, Funding acquisition, Conceptualization.

Funding

This study was supported by the National Natural Science Foundation of China (No. 82204306) and Graduate Student Innovation Project of Beihua University (No. [2024]071).

Declaration of competing interest

All authors declared that no conflict of interest existed.

Data availability

Data will be made available on request.