Department of Pharmaceutics, Rajgad Dnyanpeeth’s College of Pharmacy Bhor, Pune 412206
Transethasomes are a recently developed class of ultra-deformable nanovesicles that integrate key features of ethosomes and transfersomes, combining ethanol-enhanced permeation with surfactant-mediated elasticity. Designed for efficient dermal and transdermal delivery, these vesicles demonstrate superior skin penetration, greater drug-loading capacity, and improved stability compared with older vesicular systems. Transethosomes represent a combination of transferosomes with ethosomes, both of which are vesicular systems that combine the advantageous attributes to enhance deformability and skin permeation. Skin delivery is an effective drug transport system; however, overcoming the skin barrier is one of the most significant barriers against successful therapy, especially for plant-based products, which may have poor skin permeability. Transethosomes have emerged as one of the most promising options. However, lower viscosity and shorter skin surface retention provided the premises for the elaboration of transethosomal gels. These gels can effectively entrap unstable and high molecular weight herbal extracts, fractions, and bioactive compounds, thereby enabling enhanced drug delivery to inner layers of the skin.This review provides a comprehensive examination of transethasome composition, physicochemical properties, and preparation techniques, mechanisms of transport across the skin, characterization strategies, and therapeutic applications. A comparative analysis with other vesicular carriers, including liposomes, transfersomes, and ethosomes, is presented along with current limitations and future research directions. Evidence from preclinical studies indicates that transethasomes hold immense promise for delivering small molecules, phytochemicals, peptides, and macromolecules. Addressing challenges related to stability, large-scale manufacturing, and clinical evaluation will be essential for translation into commercial dermatological and transdermal products
Transdermal drug delivery provides a non-invasive route that bypasses hepatic first-pass metabolism, allows sustained drug release, and enhances patient compliance. However, the skin’s outermost layer, the stratum corneum, strongly restricts the permeation of hydrophilic and high-molecular-weight molecules. To overcome these challenges, researchers have developed vesicular nanocarriers capable of transporting therapeutic agents across or into the deeper layers of the skin.[1]
Over the past two decades, liposomes were the first vesicular carriers introduced for topical applications. But despite their biocompatibility, conventional liposomes displayed limited skin penetration due to their rigid phospholipid bilayer. Ethosomes, composed of high ethanol concentrations, improved penetration through lipid fluidization but suffered from vesicle instability at high ethanol levels. Transfersomes, containing surfactant-based edge activators, offered enhanced deformability yet remained sensitive to environmental stress and drug leakage.[2]
In response to these limitations, transethasomes were developed as a hybrid system combining ethanol’s permeation enhancement with the flexibility provided by edge activators. First introduced around 2012, transethasomes have since demonstrated high potential for delivering both hydrophobic and hydrophilic drugs, overcoming poor solubility, and enabling deep dermal and sometimes transdermal administration. This review outlines the structural properties, preparation methods, scientific advancements, and clinical translation prospects of this innovative delivery system.[3]
Transdermal and dermal drug delivery technologies have evolved significantly as researchers seek non-invasive alternatives to oral and parenteral drug administration. This route offers multiple advantages, including avoidance of first-pass metabolism, sustained drug release, easy termination of therapy, and improved patient compliance. However, the skin’s outermost layer the stratum corneum remains a formidable barrier to permeation, limiting the delivery of hydrophilic drugs, macromolecules, and drugs with high molecular weight. Vesicular systems such as liposomes, niosomes, transfersomes, and ethosomes have emerged to address these limitations. Liposomes, despite their biocompatibility, suffer from poor deformability and low skin penetration. Transfersomes introduced the concept of edge activators to provide elasticity, but they lack chemical stability. Ethosomes employ high ethanol concentrations to fluidize skin lipids, but such formulations often face vesicle instability and drug leakage.
In an effort to integrate the strengths of ethosomes and transfersomes, transethasomes were introduced as hybrid vesicular carriers. These vesicles combine ethanol-induced lipid fluidization with surfactant-mediated membrane flexibility, yielding superior permeation performance, higher drug solubility, and more stable vesicle structures. Since their introduction, transethasomes have gained attention for transporting a broad range of therapeutic agents, including hydrophilic drugs, lipophilic drugs, peptides, and phytochemicals.[4,5]
This review aims to provide a comprehensive and structured understanding of transethasomes, discussing their composition, mechanisms, fabrication, characterization, applications, limitations, and future potential.
Transdermal Pathways
Skin Barriers to Transdermal Delivery:
Transdermal (through-the-skin) delivery allows drugs to pass from the surface of the skin into systemic circulation. To understand this process, it's essential to know how drugs penetrate the skin and what barriers they face.
The stratum corneum is the significant barrier for the drugs to permeate, consisting of an outer layer- stratum corneum comprising keratinocytes arranged in a denser way such that no endogenous substance penetrates the skin. It is a protective barrier that prevents most drugs and foreign substances from penetrating the skin and helps maintain homeostasis. Stratum corneum's structural characteristics allow the drugs to utilize three pathways to penetrate the skin: intercellular, transcellular, and appendage pathways. These various pathways are depicted in Fig.1. [6]
Fig. 1 Pathways of transdermal drug delivery
The skin is designed to keep things out, so it has multiple protective layers. The most important barrier is the stratum corneum.[7]
1. Stratum Corneum (Primary Barrier)
2. Epidermis (Viable Epidermis)
3. Dermis
4. Additional Barriers
Methods to Overcome Barriers
Active and passive approaches deliver the drug molecules by bypassing these skin barriers. Physical and chemical approaches are a part of the active approach, thus facilitating drug delivery. Chemical approaches involve using surfactants and oleic acid (fatty acids), which disrupt the tight connection between skin layers and speed up and improve the efficiency of the drug's passage. Physical techniques of skin permeation include Sonophoresis, thermal ablation, microneedles, electroporation, and iontophoresis. By disturbing the skin membrane, the drug can travel into. This can be either done by physical mode or by chemical. In this physical approach, certain devices are used to disrupt the membrane, thus enabling the drug to penetrate deeper into the skin and, hence, reach systemic circulation more effectively. There are a few limitations of these physical devices, such as being expensive, causing skin irritation, and requiring handling experience. Therefore, the passive approach is one of the alternative techniques to overcome these limitations. These techniques utilize nanotechnology-based carriers to deliver drugs without external devices and are more patient-compliant. The nanoparticles are smaller and provide a larger surface of penetration and absorption. Based on their preparation methods, these nanocarriers can be produced in various shapes, sizes, and charges.[8,9]
The nanoparticles may be classified into multiple categories based on their composition, such as lipid, polymeric, and inorganic-based. Lipid-based nanoparticles comprise phospholipids, cholesterol, or fatty acids used in local drug delivery and cosmetics. Some lipid-based nanoparticles include liposomes, lipid nanoemulsions, SLNs, NLCs, etc., Polymeric-based nanoparticles mainly comprise polymeric micelles, polymeric nanoparticles, and dendrimers made from synthetic or natural polymers. Some polymeric based nanoparticles include nanocapsules, nanospheres, polyplex, lipomers, polymersomes, etc. Inorganic-based nanoparticles for skin drug delivery typically involve metallic nanoparticles (iron, gold, silver, silica, cerium, etc.) and carbon nanotubes. These nanoparticles help to deliver a wide range of bioactive ingredients, including high molecular weight, hydrophilic, and insoluble substances. These molecules can be targeted at specific target sites by coating the surface of the nanoparticles, thus enabling active targeting of the drug molecules. Modifying nanoparticles by adding chemical moieties such as bile salts, surfactants, ethanols, and terpenes may allow easier passage of drug molecules. The selection of nanoparticles is based on the drug molecules' characteristics and function. Figure 2 depicts the various skin barriers and the methods to overcome these barriers.[10]
Fig. 2 Skin barriers and targeting approaches
Vesicular Drug Delivery:
Vesicular systems provide an alternate approach to the delivery of drugs with fewer side effects because of the drawbacks of the physical and chemical techniques. Different transdermal delivery methods, including SLNs, lipid nanovesicles, and NLCs, each have unique features that make them suitable for delivering drugs via the skin. SLN and NLCs are neither as stable nor effective in loading drugs as lipid nanovesicles like liposomes and niosomes. Solid lipid-based SLNs may have a decreased capacity to load medications and may undergo drug ejection upon crystallization. Conversely, NLC, or second-generation lipid nanocarriers, combine liquid and solid lipids to improve stability and reduce drug leakage. Because of their tiny size and lipoidal shape, lipid nanovesicles may effectively administer hydrophilic and lipophilic medicines to the skin. Vesicular drug delivery systems are organized lipid structures with one or more bilayers in the presence of water intended to transport drugs via the stratum corneum while minimizing systemic side effects. Ethosomes, liposomes, niosomes, and transferosomes comprise these systems. One kind of second-generation vesicular system is deformable liposomes, including edge activators or penetration enhancers.[11,12]
Transethosomes
Structure of Transethosomes:
Transethosomes consist of three main components that assemble into a deformable, ultra-flexible vesicle:
Built primarily from phosphatidylcholine or other phospholipids.
Forms a bilayer membrane, similar to liposomes and ethosomes.
Serves as the main structural framework and provides a hydrophobic region that can encapsulate lipophilic drugs.[13]
Similar to ethosomes, transethosomes contain a significant percentage of ethanol.
Increases membrane fluidity and deformability
Enhances drug solubility and permeation
Helps disrupt skin lipid packing to promote penetration
Surfactants such as Tween 80, Span 20, sodium cholate, and sodium deoxycholate impart elasticity to the vesicles by lowering interfacial tension and increasing membrane deformability. The surfactant selection strongly affects mechanical flexibility and penetration depth.
Transethosomes contain an edge activator, typically a surfactant, such as: Tween 80, Span 80, Sodium cholate and Polysorbates.[14]
The aqueous medium participates in hydrating the lipid components and influences vesicle size distribution. Buffered aqueous phases may be used for pH-dependent drugs.
Optional components include:
Cholesterol (stability enhancer but reduces deformability)
Charge modifiers (e.g., dicetyl phosphate)
Antioxidants (prevent lipid oxidation)[15]
|
Component |
Role |
Effect |
|
Phospholipid Bilayer |
Main structural membrane |
Holds lipophilic drugs |
|
Ethanol (20–40%) |
Fluidizes membrane |
Enhances skin permeation |
|
Edge Activator (Surfactant) |
Increases deformability |
Squeezes through pores |
|
Aqueous Core |
Stores hydrophilic drugs |
Versatile loading |
|
Optional Stabilizers |
Improve stability |
Control rigidity |
To merge the advantages of transferosomes and ethosomes, a new delivery system known as transethosomes was introduced. Transethosomes, a third-generation vesicular carrier system, surpass transferosomes and ethosomes due to their enhanced drug-release capabilities. Figure 3 depicts the structure of transethosomes. This innovative system integrates features of both vesicles to improve transdermal drug delivery and is also applicable for ophthalmic, transvaginal, and pulmonary routes.[16]
Figure No.3. Structure of Transethosomes
Phospholipids:
Phosphatidylcholine (PC) is the most frequently used lipid because of its biocompatibility and the ability to form flexible bilayers. The lipid composition influences vesicle rigidity, drug entrapment efficiency, and release characteristics. Hydrogenated phospholipids may reduce deformability but enhance stability, whereas unsaturated lipids increase fluidity.[17]
Phospholipids are the key building blocks and vesicleforming agents derived from different sources. Based on the sources, phospholipids can be divided into natural and synthetic phospholipids. Natural phospholipids can be found in various products, including soybeans, egg yolks, and sunflower seeds. Utilizing natural unsaturated phospholipids cause the SC to fluidize, allowing APIs to permeate deeper layers. However, using saturated (hydrogenated) phospholipids improves or restores the skin's barrier function, facilitating APIs to remain intact for longer. The phospholipids can be categorized as phosphatidylcholine (PC), phosphatidylinositol, phosphatidylserine, phosphatidylethanolamine, phosphatidic acid, and phosphatidylglycerol. Due to the unsaturated properties of the hydrocarbon chain, compared to synthetic phospholipids, natural phospholipids are less stable during liposomal production.
Transethosomes formulated with unsaturated phospholipids had more skin penetration and entrapment efficiency than transethosomes made with saturated phospholipids.[18]
Ethanol:
Ethanol provides softness to the vesicle membrane and acts as a penetration enhancer.32 Ethanol concentration influences vesicle size, zeta potential, stability, enhanced skin, mucosal permeability, and entrapment efficacy. Ethanol enhances the properties of transethosomes by increasing the softness and deformability of the vesicular membrane while also serving as a permeation enhancer. The ethanol concentration significantly influences particle size, zeta potential, skin penetrability, entrapment efficiency, and stability. Ethanol concentrations typically range from 10 to 50% in transethosomal formulations. However, ethanol may cause phospholipids to dissolve more readily at higher concentrations, reducing entrapment efficiency due to its interactions with the lipid layer. Adding cholesterol to the formulation can improve stability and flexibility, even at elevated ethanol levels. [19]
The ethanol concentration is critical; too little decreases penetration enhancement, whereas concentrations above 45% may destabilize vesicles. [20]
Cholesterol:
Cholesterol in transethosomal formulation enhances their stability and improves drug entrapment efficiency. It is also noted that adding cholesterol may also increase the vesicle size of transethosomes. In several studies, a 3% concentration of cholesterol has been incorporated into formulations to stabilize the vesicular system by preventing particle agglomeration. Stabilizers play a vital role in transethosomal formulations as they help avoid particle clumping, sustain its vesicular size and cohesion, and prolong the formulation's shelf life. Cholesterol is the most frequently used stabilizer because it provides structural stability to the transethosomal system. [21]
Edge Activator:
The deformability and flexibility of phospholipid vesicles are imparted by adding an edge activator. The type and quantity of EA can alter the drug's permeability profile. Surfactants employed in the formation of TEs include Tween 20, sodium cholate, dipotassium glycyrrhizinate, bile salts, Span 80, oleic acid, and Tween 80. [22]
In a recent study, Fe-chlorophyllin transethosomes were formulated using surfactants like Sorbitan laurate 20, Polysorbate 20, Polysorbate 80, and Cetyl Stearyl Polyether-25 at low concentrations (0.1% and 0.3% w/v) alongside phosphatidylcholine and 20% w/v ethanol. Transethosomes had typical vesicular sizes between 456 and 685 nm. [23]
Transethosomes Mechanism in the Skin:
The Intercellular is the primary pathway through which the drug molecules can easily pass, thus reaching the systemic circulation. According to Fick's law of diffusion, drug permeation through the skin often occurs through a diffusion mechanism. There are also many pathways in the skin, such as diffusion shunts and appendages that can help the highly hydrophobic, large molecules or certain electrolytes to pass through the membranes. The lipoidal layer in the stratum corneum, which has a high vascularity, is vital for retaining this barrier function. Liposomal formulations cannot penetrate the epidermal layers because they contain cholesterol. The rigid compact structure of the stratum makes the liposomes fragment; thus, the drugs are released into the epidermis layer. Because of their ethanolic and non-invasive characteristics, they may enable medicines to penetrate deeper into the skin's layers or even enter the systemic circulation without affecting other cells. Transferosomes have unique characteristics that penetrate deeper tissue layers by moving from the skin's dry outer surface to the moist regions underneath, preserving their vesicular integrity and adaptability. Through pores or hydrophilic channels between cells, transferosomes permeate the skin and distribute the complete drug payload without deterioration. The unique characteristics of ethanol, such as its deformability and flexibility, allow ethosomes to deeply enter the skin, improving the absorption and penetration of drugs. [24]
Figure No 4. Mechanism of permeation of transethosomes is through the transdermal route.
Method of Preparation:
The various methods of preparation of transethosomal formulation such as Cold method, Hot method, Thin Film Hydration Method, and Ethanol Injection Method, etc. [25]
Cold Method: This method is widely used for the formulation of transethosomes, particularly suitable for heat-sensitive or thermolabile drugs. In this method, lipids such as phospholipids are mixed with ethanol (10–30%) at room temperature under constant stirring, followed by the addition of an edge activator such as Polysorbate 80 and sorbitan monooleate 80. Then, the mixture is heated to 30 C while being constantly stirred. Before adding water to the alcoholic mix, it is heated to 30°C separately. The resultant mixture is sonicated for the transethosomes to shrink in size. Ultimately, the final product is kept in a refrigerator. [26, 27]
Hot Method: This method involves dispersing phospholipids (phosphatidylcholine, phosphatidylserine, etc.) in water and heating it to 40°C in a water bath to generate a colloidal solution. In a separate process, ethyl and dihydric alcohol are combined and kept at the same 40°C temperature. Following that, the aqueous solution is gradually mixed with the ethyl alcohol and dihydric alcohol combination while being stirred constantly for 7–10 minutes. The drug is dissolved in either ethanol or water, depending on whether it is hydrophilic or hydrophobic. The resulting colloidal mixture is then combined with this API solution. The procedure is done at a consistent 40°C, and the transethosomes are sonicated to get smaller vesicles. [28,29]
Figure No.5. Method of preparation of transethosomes
Thin Film Hydration Method: This method is a commonly used technique for the preparation of transethosomes. In this method, phospholipids such as phosphatidylcholine and edge activators (Tween 80, span 80, etc.) are dissolved in chloroform or a 3:1 chloroform–methanol mixture in a round bottom flask. The mixture's organic solvent is eliminated using a rotary evaporator, leaving behind a thin coating on the flask's interior surface. N gas is introduced into the flask and set aside at room temperature for 24 h to ensure total solvent elimination. Following this, using a solution of phosphate buffer with ethanol or a combination of distilled water and ethanol, the produced lipid film is gradually hydrated for an hour. The temperature of the hydration medium should be above the lipid's gel-toliquid crystalline phase transition temperature, as this affects the size and morphology of the vesicles by influencing the packing of the surfactant molecules. [30,31]
Ethanol Injection Method: Phospholipids such as phosphatidylcholine and drugs are dissolved in ethanol while constantly stirring at 35°C to produce the organic phase. The organic phase is continually mixed into an aqueous phase comprised of water and an edge activator, constantly stirring to create a homogeneous mixture. Ethanol does not evaporate from the resultant solution since it is enclosed inside a glass vial. [32]
Characterization
Comprehensive characterization ensures quality, performance, and stability of transethasomes.
Particle Size and Polydispersity Index (PDI)
Particle size is one of the most critical physicochemical attributes governing the performance of transethosomal vesicles. Transethosomes typically exhibit particle sizes in the nanometric range, generally between 50–300 nm, depending on formulation composition, ethanol concentration, edge activators, and preparation technique. Smaller vesicles are associated with enhanced deformability, improved penetration across the stratum corneum, and higher drug-loading efficiency. Ethanol disrupts the lipid bilayer packing, enabling the formation of ultradeformable vesicles with reduced vesicle diameter. The addition of surfactants (e.g., Tween 80, Span 60, sodium cholate) further modifies membrane elasticity and contributes to the formation of smaller and more flexible vesicles. [33]
The Polydispersity Index (PDI) provides a measure of the homogeneity of vesicle size distribution. It is typically determined by dynamic light scattering (DLS), where values range from 0.0 (monodisperse) to 1.0 (highly polydisperse). For nanovesicular systems such as transethosomes, a PDI ≤ 0.3 is generally considered indicative of a uniform and stable population suitable for pharmaceutical applications. Formulations exhibiting lower PDI values typically have better long-term stability, reduced aggregation tendencies, and more predictable skin penetration behavior. [34]
Zeta Potential:
Zeta potential is a key indicator of the surface charge and stability of transethosomal vesicles. It reflects the electrical potential at the slipping plane of particles dispersed in a medium and is typically measured using electrophoretic light scattering (ELS). The magnitude and sign of the zeta potential influence vesicle–vesicle interactions, aggregation behavior, and long-term colloidal stability.
Transethosomes generally exhibit negative zeta potential values, typically ranging from −20 to −50 mV, primarily due to the presence of phospholipids and ethanol in the vesicular system. Ethanol increases membrane fluidity and contributes to the partial ionization of phospholipid head groups, thereby enhancing the negative surface charge. This high negative potential creates repulsive forces between vesicles, preventing aggregation and promoting physical stability. In addition, the incorporation of edge activators such as polysorbates or bile salts may further modify the surface charge depending on their ionic nature. [35]
Morphology (TEM/SEM)
The morphological characterization of transethosomes is essential for confirming vesicle formation, assessing structural integrity, and understanding the influence of formulation components on vesicle architecture. Transmission electron microscopy (TEM) and scanning electron microscopy (SEM) are the most widely used imaging techniques for this purpose, providing qualitative and semi-quantitative insights into vesicle size, shape, lamellarity, and surface texture. [35]
Deformability Index
Transethosomes typically exhibit higher deformability than ethosomes or classic liposomes due to the synergistic effects of ethanol and edge activators (e.g., Tween 80, sodium cholate). Ethanol imparts fluidity to the phospholipid bilayer by disrupting the hydrogen bonding and packing density of lipid molecules, while surfactants reduce interfacial tension and enhance membrane elasticity. As a result, transethosomal vesicles can traverse the stratum corneum’s tortuous lipid microchannels, which are significantly smaller than the vesicle diameter, thereby improving dermal and transdermal drug delivery.
In Vitro Release
In vitro drug release studies are essential for understanding the release behavior, membrane permeability, and kinetic profile of transethosomal formulations. These studies provide insights into how the drug diffuses from the vesicular system and can predict in vivo performance, particularly skin permeation and dermal deposition. Due to their flexible bilayer structure and ethanol-mediated fluidity, transethosomes typically exhibit sustained yet enhanced release profiles, balancing controlled drug delivery with efficient permeation. [37]
Ex Vivo Skin Permeation
Transethosomes consistently demonstrate superior permeation performance compared with conventional liposomes, ethosomes, and niosomes. This enhancement is attributed to the synergistic action of ethanol, phospholipids, and edge activators, which collectively increase membrane fluidity, disrupt stratum corneum lipid packing, and improve vesicle deformability. Ethanol acts as a permeation enhancer by extracting and fluidizing skin lipids, thereby reducing barrier resistance. Concurrently, highly deformable vesicles can traverse pores smaller than their own diameter, enabling deeper penetration into the viable epidermis and dermis. Edge activators such as surfactants (e.g., sodium cholate, Tween 80) further enhance elastic properties and contribute to the superior permeation profile. [38]
Advantages of transethosomes
Limitations of transethosomes:
Therapeutic Applications
Transethasomes have been investigated for a wide variety of therapeutic fields.
Anti-Inflammatory Agents: Transethasomes enhance dermal delivery of NSAIDs (diclofenac, ketoprofen) and anti-inflammatory phytochemicals (curcumin).
Antifungal and Antimicrobial Drugs: Enhanced delivery of terbinafine, clotrimazole, and amphotericin B improves treatment outcomes for fungal skin infections.
Dermatological Therapies: Used for Psoriasis treatments (methotrexate), Acne management (adapalene), Depigmentation (kojic acid) and Anti-aging compounds (retinoids, peptides)
Anticancer Applications: Transethasomal delivery of agents like 5-fluorouracil enhances drug localization to skin cancers while reducing systemic exposure.
Delivery of Biomolecules: Proteins, peptides, and vaccines show improved permeation due to ethanol-enhanced solubility and vesicle deformability.
Hormones and Local Anesthetics: Drugs like testosterone and lidocaine benefit from sustained release and deeper penetration.
Phytochemicals: Natural molecules with poor solubility quercetin, aloe-emodin, and resveratrol show improved dermal absorption. [40]
Comparison with Other Vesicular Systems
Transethasomes show higher deformability, stability, and penetration than traditional liposomes.
Lower ethanol content improves stability while maintaining penetration efficiency.
Addition of ethanol improves solubility and stability compared with transfersomes.
CONCLUSION
Transethasomes represent a promising evolution in vesicular drug delivery systems. Their hybrid structure combining ethanol-induced permeation and surfactant-mediated deformability results in vesicles with excellent skin-penetrating capabilities, improved drug solubilization, and enhanced therapeutic outcomes. Despite challenges related to clinical validation and large-scale manufacturing, transethasomes exhibit strong potential for advancing both pharmaceutical and cosmeceutical dermal therapies.
REFERENCES
Siddharth Kale, Sucheta Bhise, Transethasomes: An Emerging Class of Deformable Nanovesicles for Enhanced Transdermal and Dermal Drug Delivery- A Comprehensive Review, Int. J. of Pharm. Sci., 2026, Vol 4, Issue 4, 4027-4040, https://doi.org/10.5281/zenodo.19729347
10.5281/zenodo.19729347
