Part Two of a Two-Part Series

Introduction

Part One of this series established the foundational science: how skin is structured as a delivery barrier, which pathways actives use to traverse it, what physical and chemical factors govern penetration efficiency, and how chemical penetration enhancers work. Part Two turns to the technology that Nanohealth has spent fifteen years developing: carrier-based delivery systems—the platform that transforms promising actives into actives that actually perform.

Carrier systems—referred to internally at Nanohealth as the Active Carrier System (ACS) platform—operate on a shared principle: encapsulating an active ingredient within an engineered vehicle that controls when, where, and at what rate the active is released. In theory, carrier technology is substrate-agnostic; virtually any active can be encapsulated. In practice, the optimal carrier type depends on the physicochemical properties of the specific active, the target skin layer, the formulation environment, and the stability requirements of the finished product. There is no universal solution—which is why understanding the distinct characteristics of each system matters.

Four Primary Carrier Delivery Formats

1. Microemulsions and Solubilization Systems

A microemulsion is a thermodynamically stable, optically clear or near-clear dispersion with particle sizes in the range of 10–100 nm. Thermodynamic stability is the key distinguishing characteristic: unlike conventional emulsions, microemulsions form spontaneously and do not separate over time. Particle size drives optical behavior—below approximately 30 nm, the system is fully transparent; 30–100 nm produces a faint blue tint (Tyndall effect); above 100 nm, the system becomes visibly turbid.

The mechanism of action for skin delivery centers on interfacial tension reduction: microemulsion systems lower the interfacial tension between the active and the skin surface dramatically—typically to 10⁻²to 10⁻⁶mN/m versus conventional emulsions—substantially enhancing the capacity of the active to interact with and partition into the stratum corneum.

Microemulsions typically require high-HLB surfactants at meaningful concentrations to achieve and maintain their structure. This is effective from a delivery standpoint but carries a practical consideration: high-HLB surfactants can disrupt the stratum corneum's barrier function and create irritation risk in sensitive skin formulations. This limits their application in leave-on cosmetics designed for regular use.

In cosmetic practice, the primary application of microemulsion and solubilization technology is the incorporation of fragrances and essential oils into aqueous formulations—where clarity, stability, and aesthetic transparency are the priority requirements.

2. Nanoemulsions, Submicron Emulsions, and Nanostructured Lipid Carriers

This category covers a family of kinetically stable, emulsified delivery formats produced through high-energy processing—high-pressure homogenization, microfluidization, high-shear mixing, or ultrasonication—that reduces particle size substantially below what conventional emulsification achieves.

Nanoemulsions have a mean particle size of approximately 100–200 nm. Submicron emulsions span the 200–1,000 nm range. Both are opaque, white or off-white liquids composed of an active ingredient, an oil phase, an aqueous phase, and a mild emulsifier system. The distinction between submicron emulsions and nanostructured lipid carriers (NLCs) lies in the physical state of the internal lipid core: NLCs incorporate a combination of liquid and solid lipids, producing a partially crystalline internal structure that modifies active release kinetics compared to a fully liquid oil-phase system.

Delivery mechanisms include increased active solubility within the carrier (raising the effective concentration gradient at the skin surface), enhanced lipid-phase interaction with the stratum corneum (increasing intercellular lipid fluidity), and the penetration-enhancing effect of the emulsifier fraction.

Unlike microemulsions, nanoemulsions and submicron emulsions are thermodynamically unstable—they are kinetically stable systems that will eventually phase-separate. Standard cosmetic stability protocols apply. Formulations with suboptimal internal compatibility will show phase separation during stability assessment.

Key performance characteristics:

High active payload capacity—up to approximately 30% active loading is achievable in optimized systems

High skin penetration flux relative to conventional emulsion vehicles

Flexibility to co-encapsulate multiple actives within a single carrier

Tunable penetration depth via particle size and emulsifier selection

Broad formulation compatibility across product types

Nanohealth application example: The VA Retinol Nanoemulsion and Retinyl PropionateMicroemulsion utilize a submicron emulsion architecture built with a natural inulin-modified polymeric emulsifier. The polymeric emulsifier remains at the carrier surface, forming a cage-like slow-release structure. Because the high-molecular-weight emulsifier is retained at the skin surface rather than penetrating, irritation associated with the emulsifier fraction is minimized—a critical design consideration for retinoid formulations.

3. Submicron Lipid Particles (Solid and Structured)

Submicron lipid particles—including solid lipid nanoparticles (SLNs) and the structurally related nanostructured lipid carriers described above—encapsulate actives within a matrix of highly biocompatible solid or semi-solid lipids, producing particles with a mean diameter below approximately 400 nm.

The defining feature of this format, relative to nanoemulsions, is the degree of phase separation between the encapsulated active and the external medium. In a well-formulated lipid particle system, the active is genuinely isolated within the lipid matrix—preventing exchange with the external phase. This architecture provides the most robust stability protection for chemically labile actives, as the active has no contact with water, dissolved oxygen, or other reactive species in the continuous phase.

Controlled release behavior in this format is governed by the crystalline structure of the lipid matrix, which must be formulated to avoid active expulsion during storage—a phenomenon known as polymorphic transformation, where the lipid matrix undergoes recrystallization that reduces the available space for the active molecule.

Nanohealth application examples: Phenylethyl Resorcinol Microemulsion; Astaxanthin Submicron Lipid Particle.

4. Liposomes

Liposomes are the flagship format of the cosmetic carrier category—and for good reason. Their history, structural sophistication, and breadth of application make them the most extensively studied and applied delivery system in both pharmaceutical and cosmetic contexts.

History and structure

Liposomes were discovered serendipitously in 1961 by British scientist Alec Bangham and colleagues at the Babraham Institute, who observed that phospholipids dispersed in aqueous media spontaneously formed closed vesicular structures. The structural description was published in 1964; the term "liposome" came into use in 1968 and has remained standard.

A liposome is a closed spherical vesicle formed by one or more concentric phospholipid bilayers surrounding an aqueous core. Particle sizes range from approximately 30 nm to the micron scale. The bilayer membrane is approximately 4–5 nm thick. The fundamental driving force for self-assembly is the amphiphilic character of phospholipid molecules—their hydrophilic head groups face the aqueous phases (both external medium and internal core), while their hydrophobic fatty acid tails orient toward each other within the bilayer interior.

The two primary structural components are amphiphilic phospholipids—which form the bilayer—and cholesterol, which intercalates between phospholipid molecules to modulate membrane fluidity and mechanical stability. Cholesterol reduces the permeability of the bilayer and extends the temperature range over which the membrane maintains structural integrity.

Why liposomes work as delivery vehicles

The bilayer architecture of the liposome closely resembles the structure of biological cell membranes—a similarity that underpins both the high biocompatibility of phospholipid-based carriers and their ability to interact with skin lipid structures. Actives can be encapsulated in three physical locations: the aqueous core (for hydrophilic actives), the bilayer membrane (for lipophilic actives), or at the membrane-water interface (for amphiphilic actives). This versatility across polarity classes is one of the defining advantages of liposomes over alternative carrier formats.

Advantages in cosmetic formulation:

Extended dermal delivery. Liposomes can transport actives of varying polarity and molecular weight into the viable epidermis, addressing the limitation of many actives that are confined to the skin surface without a carrier.

Reservoir effect. Once deposited in the stratum corneum, liposomes act as a sustained-release depot, gradually releasing the active over an extended period—prolonging the duration of exposure at the target site.

Stability protection. Encapsulation shields chemically labile actives from degradation. Published examples include anthocyanins (improved oxidative stability in liposome encapsulation) and curcumin (improved aqueous solubility and stability via pH modulation of the internal aqueous phase).

Intrinsic skin benefits. Phospholipid-based liposomes contribute moisturizing, barrier-supportive, and emollient properties independently of the active they carry—the carrier itself has cosmetic function.

Tolerability improvement. Encapsulation within a liposome can reduce the direct skin contact of irritation-prone actives, allowing formulation at effective concentrations with a reduced irritation signal.

Nanohealth application examples: Ubiquinone Liposome; Ceramide NP Liposome; 4-Butylresorcinol Liposome; BiomimeticMulti-Ceramides Liposome.

Mechanisms of liposome-mediated skin delivery

Five mechanisms operate in parallel depending on formulation design:

Free active mechanism—The liposome acts as a reservoir, releasing free active at the skin surface, which then penetrates via standard diffusion pathways. The carrier increases the thermodynamic activity of the active at the interface.

Lipid component penetration enhancement—Phospholipids from the bilayer interact with and disrupt stratum corneum lipid organization, functioning as endogenous penetration enhancers for the released active.

Adsorption and fusion—Intact liposomes adsorb to the stratum corneum surface and fuse with corneocyte membranes, delivering their contents at the point of contact.

Intact vesicle penetration—A fraction of intact vesicles, particularly those with small particle sizes and deformable membranes, penetrate into or through the stratum corneum as intact structures.

Follicular pathway—Liposomes accumulate in follicular openings, using the appendageal route to bypass the intact stratum corneum and deliver actives into the follicular canal and surrounding dermis.

Factors that govern liposome penetration performance

Phospholipid saturation. Unsaturated phospholipids interact more effectively with stratum corneum lipids than saturated equivalents, producing greater bilayer fluidity and enhanced fusion.

PEGylation. Addition of DSPE-PEG2000 (a stealth-modification lipid) improves liposome stability and increases intradermal active content.

Surface charge. Negatively charged liposomes demonstrate reduced efficiency via the follicular pathway. For follicle-targeted delivery (relevant for scalp and hair care applications), surface charge should be designed accordingly.

Membrane deformability. Incorporation of edge activators (surfactants that increase bilayer flexibility) creates deformable liposome variants—discussed below under transfersomes.

Surface modification. Conjugation of cell-penetrating peptides or other targeting ligands to the liposome surface can enhance interaction with specific skin structures.

Critical quality attributes for liposome characterization

Particle size and distribution—Measured by dynamic light scattering (DLS). Particle size affects encapsulation efficiency, stability, and skin penetration behavior.

Morphology—Visualized by transmission electron microscopy (TEM), atomic force microscopy (AFM), environmental scanning electron microscopy (ESEM), or confocal laser scanning microscopy (CLSM).

Zeta potential—Quantifies the surface charge and predicts colloidal stability. A zeta potential absolute value above±30 mV indicates a system with adequate electrostatic repulsion to resist aggregation.

Encapsulation efficiency—The percentage of the total active in the system that is encapsulated within the liposome, as opposed to present in the external aqueous phase. This parameter affects both safety (unencapsulated active can behave differently from encapsulated) and stability.

Active loading—The ratio of encapsulated active to total formulation mass (liposome + active). This determines the practical dose that can be delivered per unit of applied product.

Validated performance data from Nanohealth

4-Butylresorcinol Liposome: Franz diffusion cell experiments using excised porcine skin demonstrated that a 0.2% 4-butylresorcinol liposome dispersion achieved approximately 66×greater skin residence than an equivalent concentration of unencapsulated 4-butylresorcinol in caprylic/capric triglyceride (GTCC) at 8 hours, and approximately 54×greater at 24 hours.

Pterostilbene Liposome (custom product): Franz diffusion cell methodology with excised porcine ear skin, 32°C, 300 rpm magnetic stirring, HPLC quantification. At equivalent active concentrations, 24-hour skin residence of pterostilbene liposome was 8.14×greater than unencapsulated pterostilbene.

Biomimetic Multi-Ceramides Liposome: Comparative ex-vivo permeation study versus a ceramide-containing cream at equivalent active concentrations. At 8 hours, the liposome format increased skin residence of: Ceramide NP by 7.5×; Ceramide AP by 8.5×; Ceramide NS/NG by 7.5×; Ceramide EOP by 7.2×.

Are Liposomes and Nanoemulsions Nanomaterials?

This question arises regularly in regulatory discussions and warrants a direct answer.

Under the European Commission's Recommendation on the definition of nanomaterials (second version), a nanomaterial is defined specifically as an insoluble or sparingly soluble solid particle with one or more external dimensions in the 1–100 nm range. The updated definition clarifies that:

The material must be a solid particle

A specific surface area criterion (below 6 m²/cm³) excludes many dispersed systems from the definition

The previous threshold flexibility clause has been removed, with a fixed 50% threshold for the proportion of particles in the nano size range

The key point: Liposomes and nanoemulsions are not solid insoluble particles. They are fluid lipid-based dispersions. They do not meet the regulatory definition of nanomaterials under current EU cosmetics regulation. This distinction is important for regulatory documentation, consumer communication, and ingredient notification compliance.

Advanced Bilayer-Based Carrier Formats

Beyond conventional liposomes, several modified bilayer systems have been developed to address specific delivery challenges. Nanohealth has developed or is developing a number of these as cosmetic ingredient platforms.

Transfersomes (Deformable Liposomes)

Transfersomes are composed of phospholipids and/or cholesterol combined with an edge activator—a surfactant (such as polysorbates, sorbitan esters, polyglycerol emulsifiers, or bile salt derivatives) that intercalates into the bilayer and disrupts its ordered packing. The result is a highly deformable membrane that can squeeze through pores in the stratum corneum approximately one-tenth the vesicle's own diameter.

Two mechanisms drive enhanced penetration: the deformability conferred by the edge activator, and—under non-occluded application conditions—a transdermal osmotic gradient generated by evaporation of water from the applied formulation, which creates a hydration gradient that pulls the vesicles inward through skin channels.

The practical limitation: edge activators with high HLB values carry a higher irritation potential than the phospholipids in a conventional liposome system. For sensitive skin formulations, this tradeoff requires careful evaluation.

Ethosomes

Ethosomes incorporate ethanol at high concentrations (20–50%) within the phospholipid bilayer system. Ethanol serves dual roles: it increases membrane fluidity and deformability, and it independently disrupts stratum corneum lipid organization, reducing barrier resistance. The combination produces systems with smaller particle sizes, higher encapsulation efficiency, and greater deformability than conventional liposomes.

Ethosomes are well-characterized in the academic literature, but ethanol at these concentrations faces consumer and formulator resistance in many cosmetic markets—particularly in Asia—where alcohol-free positioning is preferred. This limits their practical application in mainstream cosmetic formulations.

Transethosomes

A hybrid format incorporating elements of both transfersomes and ethosomes—phospholipid bilayers with ethanol and a non-ionic surfactant or penetration enhancer (cetrimonium bromide, oleic acid, polysorbates). Transethosomes show improved performance over either parent system: enhanced penetration under both occluded and non-occluded conditions relative to transfersomes; superior active residence in deeper skin layers relative to ethosomes.

The tradeoff is that the combination of ethanol and a surfactant edge activator makes transethosomes the most irritation-prone of the bilayer-based family. Their application in cosmetics is consequently the most restricted.

Niosomes (Non-Ionic Surfactant Vesicles)

Niosomes are vesicular structures formed from biodegradable, non-ionic surfactants—typically combinations of polyglycerol emulsifiers at different HLB values—that self-assemble into bilayer vesicles analogous in structure to liposomes.

Niosomes interact with the stratum corneum through adsorption and fusion, increasing the thermodynamic activity of lipophilic actives at the interface. They also modulate stratum corneum hydration by reducing transepidermal water loss, which loosens the tightly packed corneocyte architecture and increases permeability. Because niosomes incorporate high-HLB surfactants, their irritation profile sits between conventional liposomes and the deformable vesicle formats.

A variant format—deformable niosomes—uses block polyether copolymers to form vesicle carriers with enhanced membrane flexibility, enabling progressive penetration through successive corneocyte layers.

Nanohealth application examples: Isoquercitrin Niosome; Astaxanthin All-Natural Niosome; Stabilized Guaiazulene Niosome (the carrier format for Nanohealth's flagship anti-redness active).

Invasomes (Terpene-Containing Liposomes)

Invasomes combine a conventional liposomal base with a terpene or terpene mixture incorporated into the bilayer. The terpene component disrupts hydrogen bonding between lipid lamellae in the stratum corneum, loosening the intercellular lipid architecture and increasing bilayer membrane fluidity simultaneously. The result is a carrier that combines liposomal encapsulation with built-in chemical penetration enhancement.

Nanohealth application example: Myristyl Nicotinate Invasome, using phytol (an acyclic diterpene alcohol) as the terpene component. The invasome format amplifies myristyl nicotinate's skin-tone evening activity while adding phytol's independently documented anti-aging contribution—a carrier design that delivers additive benefit rather than simply a penetration increase.

Performance data: Franz diffusion cell testing using Strat-M synthetic membrane (smooth surface facing the donor compartment, 32°C). HPLC quantification at 8 hours. Myristyl Nicotinate Invasome showed 29×greater skin residence than equivalent active concentration in a conventional cream formulation at 8 hours.

Other Delivery Formats on the Horizon

Cyclodextrin Inclusion Complexes

Cyclodextrins are cyclic oligosaccharides composed of 6–8 D-glucopyranose units linked byα-1,4-glycosidic bonds, forming a truncated cone structure with a hydrophobic internal cavity and hydrophilic exterior. The cavity dimensions are precisely defined by the number of glucose units:α-cyclodextrin (6 units) has the smallest cavity, suitable for smaller guest molecules;β-cyclodextrin (7 units) is the most widely used in cosmetics;γ-cyclodextrin (8 units) accommodates larger molecules.

Cyclodextrin complexation improves active solubility, stability, and bioavailability by forming inclusion complexes that protect the guest molecule within the hydrophobic cavity. Formulations based on cyclodextrin complexes can be prepared as fully transparent systems—an aesthetic advantage in serums and clear gel formats where opacity from conventional emulsion carriers is undesirable.

Nanohealth application examples: Supramolecular Caffeine Complex; Mevalonic Acid Lactone Inclusion Complex.

Lipid Emulsions

Lipid emulsions originated in clinical nutrition as intravenous delivery systems for essential fatty acids. In cosmetic contexts, they function as oil-in-water emulsions using phospholipids as the emulsifier, with mean particle sizes of approximately 100–500 nm—placing them in the submicron emulsion range by particle dimension.

The distinction from micellar solubilization is significant: micelles have no oil-phase core (the surfactant directly solubilizes the active), while lipid emulsions contain a true oil core that substantially increases active loading capacity. The distinction from liposomes is also structural: lipid emulsions have a phospholipid monolayer at the oil-water interface; liposomes have a phospholipid bilayer surrounding an aqueous core.

Porous Polymer Microspheres

Microspheres in the 1–250 µm particle size range offer sustained, low-concentration active release by embedding actives within a polymer matrix that degrades gradually. The extended release profile is well-suited to reducing irritation from high-potency actives—delivering effective concentrations at the skin surface over time rather than as a bolus.

In cosmetic formulation, porous polymer microspheres have found application in UV filter systems (reducing the tacky sensory profile associated with some organic filters) and as carriers for botanical extracts. Release kinetics in this format are slower than nanoparticulate systems, which limits application contexts in leave-on cosmetics where rapid onset of active delivery is the priority.

Note: microspheres with particle dimensions below 100 nm may meet the EU definition of nanomaterials and require appropriate regulatory treatment.

Dendritic Polymers

Dendrimers are three-dimensional, hyperbranched monodisperse nanostructures with highly defined and reproducible architecture, typically 1–10 nm in diameter. First described by Vögtle et al. in 1978 as "cascade molecules" and named by Tomalia et al. in 1985, they consist of a hydrophobic central core, an interior branching structure, and a functionalized hydrophilic exterior surface.

Two synthesis routes are established: divergent (growth outward from the core, adding generations of branch units) and convergent (assembly from the periphery inward to the core). Both produce molecules of precisely controlled size and architecture.

For topical delivery, dendrimers offer high molecular weight uniformity, water solubility, biocompatibility, and lipid membrane interaction—the last enabling improved penetration of lipophilic actives. Published data (Manikkath et al., 2017) demonstrated that PAMAM G4 dendrimer formulation of ketoprofen, combined with ultrasound, produced transdermal flux 9.1×greater than ultrasound-assisted unformulated ketoprofen. Dendrimers are most effective for lipophilic active delivery and are not well-suited as hydrophilic active carriers.

Supramolecular Self-Assembly

Supramolecular self-assembly—the spontaneous organization of molecular building blocks into ordered structures through non-covalent interactions (hydrogen bonding, van der Waals forces, hydrophobic interactions, electrostatic forces)—underpins several of the carrier formats described above, including phospholipid bilayers and cyclodextrin complexes.

In a broader formulation context, supramolecular chemistry enables the design of responsive, structured systems—including hydrogels, inclusion complexes, and organized lipid architectures—that can be tailored for specific active delivery requirements. As a platform approach, it represents one of the most flexible tools available to cosmetic ingredient developers working at the intersection of chemistry, materials science, and skin biology.