1. Liposomes

Liposomes are spherical vesicles composed of a bilayer of phospholipids. Their similarity to the membranes of somatic cells has made them one of the most commonly used drug delivery systems. The inner core and lipid membranes can accommodate both hydrophilic and hydrophobic drugs. However, liposomes have a low stability which can lead to rapid leakage ^[1].

To overcome this limitation, it has been proposed to modify the surface of liposomes by polymer coating or cell-penetrating peptide or by conjugating the surface with polyethylene glycol. Indeed, researchers have used layer-by-layer technology based on the electrostatic interaction of polyelectrolytes to improve the stability of transdermal drug delivery systems. More specifically, dihexadecyl phosphate was used to add a negative charge to liposomes, and then multilayered liposomes were developed (with ≤10 alternating layers of cationic chitosan followed by anionic sodium hyaluronate) using the above technique. The resulting particles (size ≈ 530 nm) exhibited an alternative change in zeta potential. Using differential scanning calorimetry and transmission electron microscopy, the multilayered liposomes appeared to form a spherical polyelectrolyte complex after deposition. Moreover, observations of the size distribution after 1 week of formation showed that the particles coated with even layers of polyelectrolytes, hyaluronate and chitosan, were more stable than those coated with odd layers. When surfactant Triton X-100 was used, the number of bilayers increased and the stability of the membrane was increased. The layer-by-layer technique also changed the drug release in a sustained manner. The in vitro skin permeation study showed that the loaded multilayer liposomes exhibited similar skin permeability, which was superior to the uncoated liposomes. Therefore, the properly coated multilayer liposomes with sodium hyaluronate as humectant and chitosan may improve stability and serve as a potential transdermal drug delivery system ^[1].

Modified liposomes (transfersomes and ethosomes) are also currently used for transdermal drug delivery. Ethosomes, first described by Touitou et al. ^[2], are lipid-based carriers characterized by a higher ethanol content compared to liposomes. Ethanol can break the lipid bilayer of the skin and makes the lipid membrane loose, allowing the vesicle to penetrate into the SC and better distribute the drug in the lipids of SC. For all these reasons, ethosomes show better penetration through the SC and have a significantly higher transdermal flux ^[3].

2. Niosomes

Niosomes are vesicles formed by non-ionic surfactants and cholesterol incorporation. They are biodegradable, relatively nontoxic, and inexpensive. Since they have a bilayer, they are structurally similar, but the materials used to make them make them more stable ^[4]. Niosomes can be classified into different groups according to their size (small/large unilamellar vesicles) or the number of lamellar layers (multilamellar/small unilamellar vesicles). Their size is also a determining factor affecting the choice of route of administration. Vesicles with a size in the submicron range are suitable for intravenous or transdermal administration, whereas vesicles with a size of up to 10 μm are commonly used for per os, intramuscular and nasal administration. Small unilamellar vesicles (size from 10 to 100 nm) are prepared from multilamellar vesicles by methods such as sonication, extrusion under high pressure and homogenization under high shear. Compared to other types of niosomes, they are thermodynamically less stable and have poor loading capacity for hydrophilic drugs and a higher tendency to form aggregates. Large unilamellar vesicles (0.1–1 μm diameter) consist of a single bilayer surrounding the aqueous core and can be used for encapsulation of hydrophilic drug molecules. Multilamellar vesicles (0.5 μm to 10 μm diameter) consist of multiple bilayers surrounding the aqueous lipid compartments separately. They can be easily prepared without complicated techniques and are more stable compared to the other two types of niosomes. Moreover, they can easily accommodate lipophilic drugs due to the multilayered membranes. ^[5].

3. Nanostructured Lipid Carriers and Solid Lipid Nanoparticles

Solid lipid nanoparticles (SLN) and nanostructured lipid carriers (NLC) are lipid nanoparticles that have been thoroughly studied for application to the skin. SLNs are prepared by replacing the liquid lipid of an oil-in-water emulsion with one or a mixture of solid lipids, while NLCs are prepared using mixtures of solid lipids with liquid lipids (oils), preferably in a ratio of 70:30 to a ratio of 99.9:0.1. The resulting matrix of NLCs has a lower melting point compared to SLNs, but still, both are solid at room/body temperature ^[6].

Aqueous dispersions of lipid nanoparticles are usually incorporated into a semi-solid dermal carrier (cream or gel) for topical application. These formulations can be prepared by the following methods:

• mixing SLN/NLC with existing products
• adding viscosity improvers to the aqueous phase
• directly preparing a semi-solid formulation containing only nanoparticles in a one-step process.

Hydrogel formulations containing hydroxyethylcellulose 4000, xanthan gum, acrylate polymers and chitosan as gelling agents, also containing SLN and NLC, have already been prepared and analyzed; the results showed good physical stability. The term nanolipid gel refers to a system consisting of lipid nanoparticles incorporated into a gel base. Nanolipid gels can be formulated by adding a gelling agent to the SLN-containing dispersion ^[7].

3.1. Film Formation and Occlusive Property of NLCs and SLNs

The SC contains ≈10–20% water. If water evaporation from the skin to the atmosphere increases and the water content falls below this level, the protective layer of the SC may no longer be intact. In this case, topical formulations with occlusive properties must be applied to the SC to regenerate the water content. As a result, the SC will begin to repair itself. Occlusion reduces the evaporation of water from the skin into the atmosphere, leaving the water in the skin. The SC swells, resulting in improved permeation of medications. Unfortunately, many topical preparations that have good occlusive properties (e.g., petrolatum, fats, fatty acids, etc.) do not have a satisfactory cosmetic or aesthetic appearance. For this reason, various emulsions (w/o or o/w) have been developed to provide a middle ground between occlusive performance and skin appearance/texture. Due to their occlusive properties, emulsions are valuable as they moisturise the skin ^[8].

NLC and SLN can form a film with occlusive properties that prevent water loss by evaporation, increase skin hydration, and thus improve skin appearance, especially in conditions such as eczema. Due to their ultrafine size, NLC and SLN can provide better occlusion compared to macroemulsions ^[8][9]. The occlusive properties of SLN and NLC formulations due to film formation after application to the skin, which results in less water evaporation, have been extensively studied (Figure 1). In particular, researchers have shown that SLN have a higher occlusion factor compared to NLC formulations with the same lipid content. Moreover, when comparing NLC formulations with different oil content, the occlusion factor showed a decrease when the oil content increased ^[10].

Figure 1. High concentration of lipid (50–60%) present in NLC formulation act as occlusive agent and is responsible for retaining the moisture in the SC ^[11].

A group of researchers compared the first NLC-containing cosmetic product to hit the market, Cutanvoa Nanorepair Q10, with a conventional o/w cream without NLCs ^[12]. The results indicated that Cutanvoa Nanorepair Q10 was more efficient, achieved long-term stability after incorporation into xanthan gum hydrogels, and exhibited higher skin hydration without irritation ^[13].

4. Nanoemulsions

The term nanoemulsion is used to describe a kinetically or thermodynamically stable liquid dispersion containing the oil and water phases in combination with a surfactant. Depending on their composition, there are three different types of nanoemulsions: water in oil, oil in water and bicontinuous. Their dispersed phase (small particles or droplets of 50–200 nm) has a very low interfacial tension between oil and water. Their lipophilic core surrounded by a monomolecular layer of phospholipids makes them more suitable for the delivery of lipophilic drugs. Nanoemulsions do not exhibit sedimentation, coalescence, foaming and flocculation like emulsions of macromolecules. On the contrary, they are transparent or translucent and exhibit properties such as low viscosity, high kinetic stability, large interfacial area and high solubilization capacity. In skin care formulations, they can provide rapid skin penetration, active ingredient transport and hydration ^[15][16].

5. Gold Nanoparticles

Gold nanoparticles or nanogold (5–400 nm in diameter) are extremely stable, biocompatible, and noncytotoxic particles. Their interparticle interactions and assembly play an important role in determining their properties. Their shape (nanosphere, nanoshell, nanocluster, nanorod, nanostar, nanocube, branched and nanotriangles), size, dielectric properties and environmental conditions have a strong influence on their resonance frequency. Their color ranges from red to violet/blue and is almost black due to aggregation. They are stable in liquid or dried form and do not bleach after staining on membranes. Gold nanoparticles are considered beneficial in formulations due to their high drug loading capacity and easy penetration into the target cell due to their small size and large surface area, shape and crystallinity, but also due to their properties, i.e., acceleration of blood circulation, anti-inflammatory and antiseptic effect, improvement of skin firmness and elasticity, retardation of the aging process and vitalization of skin metabolism ^[15].

6. Nanospheres

Nanospheres (10 to 200 nm in diameter) are spherical particles with core-shell structure. They can be crystalline or amorphous. Nanospheres can be divided into two categories: biodegradable (gelatin, modified starch and albumin) and non-biodegradable (polylactic acid). The active ingredient can be entrapped, dissolved, attached, or encapsulated within the polymer’s matrix system, protecting it from chemical and enzymatic degradation. As drug delivery systems, they have great potential as they can entrap poorly soluble or absorbed labile biological agents, enzymes and genes. In cosmetics, they are used to deliver active ingredients into the deeper layers of the skin so that they can exert their effects more precisely and efficiently at the affected site. They play an important role in protecting against actinic aging and are mainly used in moisturizers, anti-wrinkle and anti-acne creams ^[15].

Many nano-formulations are commercially available ^[17][18]; Table 1 summarizes those with hydration currently on the market.