REVIEW

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Progress in Lipid and Inorganic Nanocarriers for Enhanced

Skin Drug Delivery
Lamyaa Albakr, Hongyuan Du, Xiyuan Zhang, Himanshu Kathuria, Ahmed Fahmi
Anwar-Fadzil, Nial J. Wheate, and Lifeng Kang*

delivery systems are designed to deliver

New advancements in nanocarrier technologies are revolutionizing the delivery of the active ingredient to local skin tissue.[1]
drugs through the skin, allowing for precise treatment with better absorption, Different strategies have been studied to
stability, and bioavailability. This review investigates lipid and inorganic nano- develop effective skin drug delivery (SDD)
systems.[2] Among these approaches are
carriers like liposomes, ethosomes, and inorganic nanoparticles and assesses
chemical enhancers such as alcohols, sur-
their potential for delivering drugs through the skin. It emphasizes the mech- factants, and fatty acids that interact with
anisms that enable controlled release and deeper skin penetration, which are the skin’s lipids,[3] thus aiding in the trans-
crucial for ensuring effectiveness in clinical applications. The review synthesizes dermal penetration of the therapeutics,
existing research, acknowledging that only few nanocarriers are successfully although at the risk of skin irritation.[4]
Peptide-based biological enhancers intro-
deployed in clinical settings. By offering a comprehensive overview, it sheds light
duce temporary poration in the skin which
on the progress and future obstacles to using nanocarriers for drug delivery helps in biomolecule absorption with min-
through the skin. imal cytotoxicity. Physical enhancement
devices, such as microneedles (MNs) and
iontophoresis (passing weak electrical cur-
1. Introduction rent through the skin), temporarily disrupt skin integrity to pro-
mote drug delivery.[5]
According to the US FDA, transdermal delivery systems are Each method offers unique advantages and challenges,
designed to deliver an active ingredient (drug substance) across suggesting that a multipronged approach could optimize trans-
the skin and into the systemic circulation. In contrast, topical dermal drug delivery. Nanocarriers, encompassing nanoemul-
sions, liposomes, and inorganic nanoparticles (NPs), show
potential by enhancing drug solubility, stratum corneum (SC)
L. Albakr, X. Zhang, A. Fahmi Anwar-Fadzil, N. J. Wheate, L. Kang hydration, lipid fluidity, and modifying drug permeation path-
School of Pharmacy ways. Their efficacy is influenced by their physicochemical prop-
Faculty of Medicine and Health
University of Sydney
erties, including: size, charge, and shape.[6]
Sydney, NSW 2006, Australia Advancing nanotechnologies has led to the development of a
E-mail: [email protected] spectrum of different nanocarriers for the better design of drug
L. Albakr formulations. Drug nanocarriers have shown promise in devel-
Department of Pharmaceutics oping topical and transdermal drug delivery systems for thera-
College of Pharmacy peutic and diagnostic applications. Using nanocarriers to
King Saud University
Riyadh 11451, Saudi Arabia
deliver drugs to the skin has several advantages, including
enhanced skin penetration, targeted drug delivery, improved
H. Du
Department of Medical Genetics drug stability, and increased drug bioavailability.
Tongji Medical College
Huanzhong University of Science and Technology
Wuhan 430030, China 1.1. Drug Permeation Routes Through Skin
H. Kathuria
Nusmetics Pte. Ltd. To optimize drug delivery, it’s essential to understand the biolog-
3791 Jalan Bukit Merah, E-Centre@Redhill, Singapore 159471, ical structure of the skin, which consists of three layers, namely,
Republic of Singapore the epidermis, dermis, and hypodermis. The SC in the epidermis
The ORCID identification number(s) for the author(s) of this article acts as the first barrier to drug penetration, as shown in Figure 1.
can be found under https://doi.org/10.1002/anbr.202400003. Active ingredients, and the other chemical excipients in a formu-
© 2024 The Authors. Advanced NanoBiomed Research published by
lation, can traverse this barrier through three main routes: inter-
Wiley-VCH GmbH. This is an open access article under the terms of cellular, transcellular (also known as intracellular), and
the Creative Commons Attribution License, which permits use, appendageal (or follicular).
distribution and reproduction in any medium, provided the original The intercellular route serves as the primary pathway for drug
work is properly cited. penetration and involves the diffusion of molecules between cells
DOI: 10.1002/anbr.202400003 within the SC. In this context, the mechanical properties and

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Figure 1. Different types of nanocarriers for topical and transdermal drug delivery. Created with BioRender.com.

flexibility of nanocarriers that are used for SDD are critical. 1.2. Enhanced Drug Permeation
Flexible polymer-based nanocarriers have demonstrated a greater
ability to penetrate via this route, while rigid carriers, such as The cutaneous membrane serves as a multifaceted barrier, func-
metal NPs, face challenges due to their inflexibility.[7] tioning not only as a defense against microbial invasion but also
In contrast, the transcellular route offers the most direct but as a shield against transepidermal water loss. These features
also the most challenging pathway. For this mode of delivery, present tough challenges to effective transdermal and topical
nanocarriers need to overcome both lipophilic and lipophobic drug delivery. To address these obstacles, an array of both chem-
barriers within the skin. Nanocarriers with a high degree of ical and physical modalities have been explored.
amphiphilicity can be particularly useful for this pathway.[7] Chemical methods encompass passive penetration enhance-
The appendageal route leverages the skin’s hair follicles and ment, which employs advanced formulation strategies such as
glandular ducts for penetration. However, this route is limited supersaturation, microemulsion systems, and liposomal encap-
since these structures account for a small fraction of the skin’s sulation to increase drug permeation. Another chemical strategy,
total surface area. Importantly, the size of nanocarriers has been known as prodrug modification, entails the chemical alteration of
found to impact their penetration depth and selective targeting the parent drug molecule to enhance its lipophilic characteristics,
when delivered this way. Studies have shown that smaller par- thereby facilitating greater penetration through the lipid-rich
ticles penetrate deeper, and the nanocarriers trapped within outermost layer of the skin called the SC.[9] Examples include
the space between the hair follicle and adjacent tissue can act modification to corticosteroids like triamcinolone and betame-
as a drug depot for sustained release.[8] thasone, which resulted in marked improvements in their topical
Beyond the epidermis, the dermis contains physiological efficacy. Likewise, chemical enhancers like fatty acids, alco-
structures like the sweat glands, the base of the hair follicles, hols,[10] and terpenes,[11] can be included in a formulation to
and the blood vessels, which serve the nutritive and thermoreg- lower the skin’s barrier function.
ulatory functions of skin. These can provide alternative pathways With regard to physical approaches, techniques, such as ion-
for substances that find other routes challenging.[7] tophoresis, which utilizes low-amperage electrical currents;

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electroporation, which employs brief high-voltage pulses to gen- delivered to the skin. For example, a study concluded that a lipid
erate aqueous channels; sonophoresis or ultrasound, which lev- NP formulation of isoflavone orobol using nanostructured lipid
erages high-frequency acoustic vibrations; and MNs, which carriers (NLCs) made of shea butter was able to improve the sta-
induce microscopic perforations in the SC, have been employed bility of orobol and enhance its delivery into the skin. The resul-
to increase drug permeability through skin.[5,10] tant particles showed a nanosized spherical morphology,
Nanotechnology-based strategies offer another method for maintained the stability of orobol for up to 28 days, and signifi-
SDD. Lipid-based NPs have gained attention for their ability cantly increased the deposition of orobol in a clinical study.[17]
to interface with lipid bilayers, thereby enhancing both the quan-
tity and depth of drug penetration. Empirical studies have dem- 1.5. Increased Drug Bioavailability
onstrated the effectiveness of lipid nanocarriers in facilitating the
transdermal delivery of a range of different active ingredients, As a result of increased stability, sustained or prolonged release,
including 5-aminolevulinic acid (5-ALA) for topical photody- and enhanced accumulation in the target area of skin, nanocar-
namic therapy and tocopherol acetate (TA) as a humectant.[12] riers can improve the bioavailability of drugs. Drug bioavailability
Ethosomal gels incorporating TA, for example, demonstrated can be improved by optimizing the drug’s physiochemical prop-
superior skin penetration, with 44.55% of the formulation per- erties via nanocarrier delivery. An example is tea catechins,
meating the skin and with 51.20% still retained in the skin at which have therapeutic potential for skin disorders, but low topi-
24 h after application.[13] Additionally, lipid NPs can interact syn- cal bioavailability due to low lipophilicity. Lipid-based nanofor-
ergistically with the SC, forming a hydrophobic layer on the skin, mulations of tea catechins enhanced their bioavailability
thereby reducing keratinocyte aggregation, and enlarging inter- through increased lipid solubility, resulting in improved drug
cellular spaces, thereby enhancing transdermal drug delivery.[14] retention.[18]
These assorted strategies collectively aim to strengthen the safety, In general, nanocarriers for SDD, based on building material,
and efficiency of topical and transdermal drug delivery mecha- can be classified into two main categories: lipid nanocarriers and
nisms and are the focus of ongoing, comprehensive research inorganic nanocarriers, as shown in Figure 1. In recent years,
endeavors. there has been significant research focus on lipid-based nanocar-
Nanocarriers represent a significant advancement, particularly riers, as evidenced by the consistently high number of publica-
in treating skin disorders, a like skin cancer. One notable study tions dedicated to this topic.
demonstrated that a nanofibrous scaffold containing molybde-
num NPs reduced the viability of skin cancer cells by more than
50% through apoptosis. In-vivo trials in zebrafish further dem- 1.6. Methods of Transdermal and Topical Nanocarriers
onstrated a more than 30% reduction in cancer progression Preparation and Scale-up
within 14 days, while minimizing harm to healthy cells.[15]
In this review, we have surveyed a variety of nanocarrier prepa-
ration methods, each offering unique advantages for enhancing
1.3. Controlled Drug Release Rate SDD. These methods are critical for the development of nano-
carriers with optimized physicochemical properties, which influ-
Nanocarriers can provide controlled release of drugs delivered ence drug release, stability, and skin permeation efficiency.
into the skin. By encapsulating the drug within a nanocarrier, Lipid-based nanocarriers, such as liposomes and ethosomes,
the release rate of the drug can be regulated, allowing for slower can be prepared by thin-film hydration, reverse-phase evapora-
and sustained release over time. This helps to improve the drug’s tion, or ethanol injection methods. These vesicles work by encap-
effectiveness and minimize unwanted side effects. sulating drugs within their bilayer structures.[13] Solid lipid NPs
The controlled release can also help improve the drug’s bio- (SLPs) and NLCs are typically synthesized using high-pressure
availability, as the sustained release can help to maintain thera- homogenization or microemulsion techniques to achieve a solid
peutic levels in the body over an extended period. For example, a matrix that can stably incorporate lipophilic drugs. Scale-up of
stable formulation of benzoyl peroxide (BPO) uses solid lipid these lipid-based nanocarriers is feasible using large-scale
nanocarriers (SLN)s to reduce side effects. The BPO-SLN showed homogenizers and controlled microfluidic systems to ensure
controlled drug release, decreased skin irritation, and increased batch-to-batch consistency.[16,17,19]
antibacterial activity when compared with the marketed Methods for the preparation of inorganic nanocarriers com-
product.[16] monly involve a reduction reaction in solution to produce metal
NPs of gold, silver, iron, and copper. Often these synthesis meth-
1.4. Improved Drug Stability ods employ stabilizing agents to control particle size and prevent
aggregation.[20] Silica NPs are synthesized using sol–gel pro-
Nanocarriers can increase the stability of drugs delivered to the cesses that allow for the creation of mesoporous structures capa-
skin. Encapsulating a drug within a nanocarrier can protect it ble of high drug loading. The scaling up of inorganic NP
from degradation, oxidation, or other chemical changes that synthesis can be achieved through continuous flow reactors.[21]
can reduce its potency. This helps to improve the shelf-life Carbon-based nanocarriers, such as carbon nanotubes (CNTs)
and overall stability of the drug, ensuring that it remains effective and graphene, are produced primarily through chemical vapor
over time. Additionally, nanocarriers can protect drugs from deposition and exfoliation. Other methods include laser ablation,
being quickly metabolized or eliminated from the body, helping discharge, and thermal chemical vaporization techniques that
to improve their bioavailability and overall effectiveness when offer precise control over particle formation, while hydrothermal

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and detonation methods enable carbon-based nanocarrier syn- the keywords were “inorganic nanoparticles,” “gold nanoparticles,”
thesis under unique pressure and temperature conditions. “iron nanoparticles,” “silver nanoparticles,” “silica nanoparticles,”
Scale-up methods for carbon-based nanocarriers often involve “cerium nanoparticles,” “copper nanoparticles,” “iron nanopar-
transitioning to industrial-grade chemical vapor deposition reac- ticles,” “molybdenum nanoparticles,” “carbon nanoparticles,”
tors and optimizing the parameters for large-scale hydrothermal “carbon nanotubes,” “carbon nanodiamonds,” “fullerene,”
reactors to maintain the quality and uniformity of the NPs.[22] and “graphene”.
Nanocarriers combined with other delivery approaches, such The above keywords, or their chemical formula, or their syn-
as MNs and ionophoresis, can help to overcome complex chal- onyms, were combined with the terms “skin drug delivery,”
lenges in topical drug application. In addition, combining differ- “transdermal,” or “dermal”. The full texts were located after iden-
ent nanocarrier approaches, referred to as nanohybrids, can also tifying relevant articles, and the duplicates were removed. The
solve the delivery hurdles for some drugs. For example, Huang articles were further screened to exclude those with inaccessible
et al. developed a topical hydrogel with antifungal and antibacte- full texts and/or irrelevant to this review to obtain 132 articles for
rial action consisting of silver NPs and graphene oxide.[23] analysis.
Likewise, Schnaider et al. developed an antimicrobial hybrid
hydrogel of nanofibrillar silk and silver NPs. The silver NPs
in the hydrogel provided antimicrobial activity without causing 3. Lipid Nanocarriers
cell hemolysis and cytotoxicity, which is observed with conven-
Lipid nanocarriers have been used for SDDs for a long time.
tional silver NP treatments. Lan et al. demonstrated topical can-
They are made from lipids (fats or oils) and can take various
cer immunotherapy using MNs loaded with lipid NPs containing
forms, including liposomes, penetration-enhancing vesicles
anticancer drugs. The NPs were pH-responsive with tumor-
(PEVs), SLNs, NLCs, lyotropic nanocrystals, and microemul-
targeting capability, while the MN provided minimally invasive
sions. These nanocarriers transport drugs, proteins, and other
direct drug delivery to the tumor via the skin.[24]
active ingredients to specific cells or tissues inside and/or via
Nanocarriers can exhibit intrinsic functional activity. For
the skin. Different nanoliposomes and PEVs can be obtained
example, silver NPs have antimicrobial and antidiabetic proper-
with high flexibility and deformability by adjusting their compo-
ties and can be used as a delivery system for therapeutic agents to
sition to improve skin permeation. For a detailed comparison of
speed up wound healing in diabetic patients.[25] Additionally, fla-
the composition and mechanism of permeability of lipid-based
vosomes have anti properties and have been used in delivering
versus inorganic-based nanocarriers, see Table 1.
antiwrinkle agents in cosmetics.[26]
Nanoemulsions, another form of lipid nanocarriers, are
A comprehensive analysis of advancements in the domain of
known for their small droplet size and enhanced drug delivery
nanocarriers for topical and transdermal drug delivery, as well as
capabilities. They offer the advantages of homogeneity, stability,
SDD in general, can be found in several review articles. Yu et al.
and often exhibit higher drug penetration rates. In addition,
(2021) reviewed a spectrum of nanocarriers, emphasizing their
other lipid nanocarriers like SLNs and NLCs are designed to pro-
potential to permeate the SC.[27] Qu et al. (2022) spotlight the
vide higher encapsulation rates and greater stability. The most
advantages of combining nanocarriers with MNs for skin disease
used lipid nanocarriers for SDD, including microemulsions,
treatment.[28] A paper by Tapfumaneyi et al. (2022) focused on
are discussed below.
advancements in topical and transdermal delivery systems,
emphasizing the role that nanotechnology-derived carriers play
in skin treatment.[29] Finally, An et al. (2020) explored the trans- 3.1. Liposomes
dermal delivery of nanocarrier-embedded hydrogels enhanced by
electrodialysis-driven iontophoresis.[30] Liposomes are spherical structures that contain a hydrophilic
In light of such pivotal reviews, our narrative offers a unique core encapsulated within a phospholipid bilayer (Figure 2).
angle. Apart from discussing the different types of nanocarriers With varied compositions, liposomes can be modified into other
for SDD, emphasizing their clinical status, we introduce a novel types of vesicular nanocarriers, such as niosomes, transfero-
classification system categorizing these carriers based on their somes, ethosomes, and pharmacosomes.[31]
components, such as lipid based or inorganic based. This review They have been used to deliver a wide range of drugs to the
also presents recent developments, advantages, and limitations skin, including antibiotics, anti-inflammatory drugs, and anti-
of these nanocarriers in SDD, providing a fresh and comprehen- cancer agents. Liposomes can be engineered to be pH sensitive,
sive perspective on the subject. which allows them to release their drug content in the skin
through a drop in pH, increasing skin penetration and retention
of the drug. Factors affecting the penetration of liposomes
2. Literature Review Method through the skin include the type of phospholipids, the presence
of cholesterol or fatty acids, the size of the liposomes, the surface
A search in the PubMed database from 2015 to 2023 was made charge, and the presence of other excipients.[32]
using the following search strategy. For lipid nanocarriers, The optimal particle size of liposomes for skin penetration is
the keywords were “liposomes,” “flavosomes,” “ethosomes,” generally considered to be around 100–200 nm. However, the
“transethosomes,” “proposomes,” “niosomes,” “ufosomes,” charge on the liposomes used in SDD can vary depending on
“glycerosomes,” “hybrid lipid-polymer nanocarriers,” “solid lipid the application and the delivered drug. Negatively charged lipo-
nanoparticles,” “nanostructured lipid nanocarriers,” “lipid somes, or anionic liposomes, have been shown to improve hydro-
nanoparticles,” and “cubosomes”. For inorganic nanocarriers, philic drug delivery and increase drug bioavailability. For

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Table 1. Lipid and inorganic nanocarriers: composition, penetration mechanisms, common applications, and advantages.

Composition Method of Mechanism of Common application Advantages References

preparation permeation
Lipid Nanocarriers
Liposomes Phospholipids Thin-film hydration Absorption through the Treatment of primary Enhances skin [18,35]
method cutaneous layer or sweat axillary hyperhidrosis penetration.
Cholesterol Sonication pores, enhanced delivery (PAH) Carries both water-
using multilamellar soluble and lipid-soluble
Extrusion
liposomal nanovesicles drugs
Reverse-phase carrying both water-
evaporation soluble and lipid-soluble
drugs
PEV
Niosomes Similar to liposomes but non-ionic Thin-film hydration Increased skin Cosmetics Low cost [22a]
surfactant instead of phospholipids method permeability by disturbing Fibromyalgia High stability
the SC syndrome
Proposomes Propylene glycol (PG) Cold mixing process Enhanced skin Treatment of skin Improved absorption of [49]
with different permeability disorders such as chemicals with different
concentrations of psoriasis, atopic log P values
Soya phosphatidylcholine (SPC) SPC and PG, critical Transfollicular route of dermatitis, and Stable for at least
micelle penetration baldness 6 months
concentration
Effective for targeted
measured by surface
topical drug delivery
tension method
Ufosomes Cholesterol Thin-film hydration Enhances skin Topical delivery of Economical preparation [56]
method penetration due to the clotrimazole for due to low-cost of fatty
lipophilic nature of the fungal infections acids, improved stability
vesicles and permeability, high
Sodium oleate Interacts with the SC to entrapment efficiency
enhance topical
bioavailability of
clotrimazole
Flavosomes Phospholipids Thin-film hydration Enhanced skin Topical delivery of Improved solubility and [26]
method followed by permeation when anti-inflammatory permeation of NSAIDs
Cholesterol sonication compared with drugs Potential to reduce
transfersomes due to the gastrointestinal side
deformable nature of effects associated with
flavosomes oral administration of
NSAIDs
Edge activator
Flavonoids (Quercetin,
Dihydroquercetin),
Glycerosomes Dipalmitoylglycerophosphatidylcholine, Thin-film hydration Enhanced skin deposition Dermal and High drug loading [53]
method followed by and permeation of anti- transdermal drug capacity
sonication inflammatory drugs delivery, particularly
Cholesterol Suggests improved for diclofenac Improved stability, and
bioavailability for reduced cytotoxicity
Glycerol transdermal delivery Sustained release and
enhanced penetration
through the skin
Bilosomes Bile salts Thin-film hydration Enhanced skin Topical treatment of Overcoming the outer [64]
Span 60 technique permeability and acne skin barrier, enhancing
improved drug delivery drug accumulation in
Cholesterol
through the outer skin the epidermis and
skin barrier for effective dermis layers, increased
topical therapy local activity while
reducing systemic
absorption

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Table 1. Continued.

Composition Method of Mechanism of Common application Advantages References

preparation permeation
Cerosomes Ceramides Thin-film hydration Enhances drug deposition Topical delivery of High entrapment [68]
method and skin hydration, water antifungal agents efficiency
Phospholipids, uptake in SC leading to Protective and Formation of nanosized
swelling and structural regenerative skin vesicles
alterations activity
Surfactants (e.g., Brij52, Brij97) Prolonged residence
time at the site of action
Stearylamine Improved topical drug
efficacy
Ethosomes Ethanol Cold method Increases the penetration Cosmetics High penetration [18]
technique of drugs due to increased
Phospholipids Ethanol injection SC lipid fluidity and its Collagen delivery High loading of drugs
method deformable feature that
Skin regeneration
allows it to squeeze into
the SC
Transethosomes Ethanol Thin-film hydration Sustained release from Effective delivery Deformable vesicles [18,45]
Phospholipids method transethosomal gels system for skin with a high entrapment
diseases such as efficacy, able to improve
Edge activators (Such as Tween 20,
atopic dermatitis or drug release and
Tween 80, Span 60, Span 65, Span 80,
psoriasis penetration into the skin
sodium cholate, and sodium
deoxycholate)
Lipid NPs
SLN Lipids: Precirol ATO 5 Solvent evaporation SLN have lower Acne Potential sustained [16,17,19]
method permeation rates which release
Surfactants: Tween 80 Hot result in increased skin
homogenization drug deposition, leading
followed by to reduced skin irritation
sonification method when compared with
marketed products
Microemulsion
method
PLN Glyceryl behenate Lipid melt- The small size and lipid Used in targeted drug Increased stability and [81]
emulsification composition facilitate delivery systems, controlled drug release
Glyceryl Palmitostearate combined with the penetration through the especially for poorly Improved patient
solvent injection outer skin barrier, thus soluble drugs, compliance due to non-
Phospholipids (ISL)
technique enhancing drug delivery enhancing their invasive routes of
HA-Polyethylene glycol-Linoleate to deeper tissue layers bioavailability and administration
conjugate (HA-PEG-LOA) therapeutic efficacy
Sorbitan monooleate (Polysorbate 80)
NLC HA Lipid melt- Enhanced percutaneous Transdermal delivery Small particle size [76]
Linoleic acid (LOA) emulsification penetration due to HA of local anesthetics High drug encapsulation
combined with the modification, facilitating for pain management efficiency
solvent injection transdermal drug delivery
Propylene glycol (PEG), Sustained drug release
technique
Improved stability
Enhanced anesthetic
effect
Nanoemulsion Benzalkonium chloride Emulsification using Destabilization and lysis Burn wound Broad-spectrum [96]
Tween 20 high shear of microbial outer treatment, exhibiting antimicrobial efficacy,
conditions to membranes broad of antibacterial prevention of burn
Ethanol
produce droplets and antifungal wound progression,
Glycerol that fuse with lipid properties inhibition of neutrophil
EDTA layers in microbial infiltration and
membranes inflammation,
Highly refined soybean oil
preservation of hair
Water follicles, conducive to
wound healing

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Table 1. Continued.

Composition Method of Mechanism of Common application Advantages References

preparation permeation
Lyotropic liquids
Hexasomes Amphiphilic lipids (e.g., glycerides, Mixing amphiphilic Facilitates solubilization Topical and High versatility, [83]
phospholipids) substances with an and trapping of transdermal drug biocompatibility
aqueous phase and hydrophilic, lipophilic, delivery
Water stabilizers, high- and amphiphilic guest Treatment of skin Ability to protect drugs
pressure molecules; protects diseases from degradation
homogenization, against oxidation or
Dermatocosmetology Improve drug solubility
and ultrasonication hydrolysis
and bioavailability
Minimize drug toxicity
Cubosomes Glycerol monooleate (GMO) Pre-loaded or post- Encapsulating and Topical delivery of High peptide [87]
loaded protecting protein and antimicrobial encapsulation efficiency
peptide drugs from peptides for
degradation treatment of bacterial
infections
Poloxamer 407 Hydrotrope Enhancing skin Potential as a Protection from
methods penetration and delivery photosensitizer proteolytic degradation
of active substances Delivery for Suitable for topical
photodynamic applications with no
therapy observed skin irritation
Inorganic Nanocarriers
Carbon Nanomaterials
Graphene Exfoliated graphene oxide (GO) sheets Simple solution Controlled release of Controlled drug Acts as a reinforcing [135]
Polyvinyl alcohol (PVA) casting method drugs (e.g., anti- release of NSAID agent to control drug
from aqueous inflammatory release, with potential
precursors ketoprofen), with for applications in
diffusion rate and release transdermal drug
determined by PVA and delivery
GO loading ratios.
CNT Carboxylated CNT Laser ablation Penetration followed by Drug carrier for High loading, enhanced [22a,126]
method passive diffusion across topical chemotherapy transdermal penetration
PEG Discharge method the lipid bilayer, can act as Enhancing skin Electroconductive for
a ‘nanoneedle’, penetration for iontophoresis
permeation via hydrophobic drugs applications
adsorption and
Thermal chemical Can be used as
subsequent desorption
vaporization electrodes
technique
Sonication in N,N-
dimethylformamide
Stirring with oxalyl
chloride
Fullerene C60 Hydrothermal Can penetrate across the Anticancer Enzyme inhibition [22b]
method SC barrier into the dermis
Resistive heating of and accumulate in hair Antimicrobial Targeted drug delivery
graphite follicles; endocytosis by
Photodynamic Diagnostic imaging
human keratinocytes and
therapy (PDT)
fibroblasts
Can induce ROS-
mediated cell death
Enzyme inhibition
Targeted drug
delivery
Diagnostic imaging

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Table 1. Continued.

Composition Method of Mechanism of Common application Advantages References

preparation permeation
Nanodiamonds CND Detonation method UV radiation absorption Preventing UV- Feasible and safe for UV [22c]
and scattering induced skin damage protection
Laser ablation (i.e.used in Efficient reduction of UV
sunscreens) radiation
Ceramic bead Significant protection
milling against UV-induced
damage in cell cultures
and mouse models
Wet chemical No photocatalytic
milling activity
Thermal fluidizing
bed methods
Silica NPs 3-mercaptopropyltrimethoxysilane Air bubbling and Enhanced delivery into Targeted drug PEGylation enhances [116]
stirring method hair follicles with delivery to hair targeted delivery into
PEGylation, especially follicles for hair follicles
PEG 5000 Da showing conditions like
deeper penetration alopecia and acne
5-(iodoacetamido) Grafting copolymers Intended for topical Controlled release and
onto MSNPs cutaneous protection of labile
application, notably compounds until they
for delivering reach the skin
antioxidants, like Can trigger release
quercetin, to the skin based on temperature at
the application site.
Metal NPs
Gold NPs Dodecanethiol coated AuNPs Coarse grained Neutral hydrophobic Transdermal drug Maximum permeability [97]
molecular dynamics AuNPs disrupt the lipid delivery systems and for neutral, 2 nm wide
simulations bilayer and penetrate cosmetics AuNPs
deeply, while charged Ability to induce
AuNPs adhere to the structural changes in
surface of the bilayer bilayer
Silver NPs Silver NPs (AgNPs) Reduction reaction Shape-dependent Antimicrobial Antimicrobial activity [20a]
(e.g., by a permeation where rod- applications in Biocompatibility
polysaccharide) shape silver NPs have the hydrogels for wound
Cytocompatibility
highest penetration. healing (e.g., diabetic
foot) In vivo wound healing

Iron NPs Dextran-coated iron oxide NPs pH-triggered in situ Heated upon laser Topical photothermal Favorable for application [107]
gel-forming method irradiation and was therapy (PTT) of skin retention.
applicable for topical PTT cancer Effective as a topical PTT
agent for the treatment
of skin cancer.
Molybdenum Molybdenum trioxide (MoO3) Electrospinning of Facilitates localization Targeted skin cancer Low toxicity [15]
NPs polycaprolactone and targeted delivery of therapeutics
Polycaprolactone (PCL) nanofibers with chemotherapeutic drugs Antibacterial Antimicrobial properties
Molybdenum applications
Trioxide (MoO3) NP
Enzyme cofactor for Potential for
metabolic processes photothermal therapy
Significant tumor cell
reduction in treated
samples

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Table 1. Continued.

Composition Method of Mechanism of Common application Advantages References

preparation permeation
Copper NPs Cu2(OH)PO4, CuI, CuO Synthesis involves Photothermal conversion Tumor-oxidative High biocompatibility [110]
surface mediation effect for on-demand drug therapy
with polymers release, ROS generation Antibacterial
for antibacterial activity, applications
Fenton reaction for
Drug delivery Photothermal and
cancer therapy
photodynamic effects for
antibacterial efficacy
Tissue engineering Tissue regeneration
capabilities
Cerium NPs CeO2 Hydrothermal Poorly permeable to intact Treatment of Low cost [114]
synthesis using skin oxidative stress Unique crystal structure
cerium ammonium diseases
Ability to reduce
nitrate
oxidative stress
Stimulative effect on
mineralization and cell
proliferation

Figure 2. Schematic representation of the different types of vesicular nanocarriers. Reprinted with permission.[31] Copyright 2021, American Chemical
Society. This content is adapted under the terms of the CC-BY-NC-ND 4.0.

example, research by Maione-Silva and colleagues revealed that a combination of curcumin, a natural compound with anticancer
negatively charged liposomes as a delivery system for vitamin C properties, and small interfering RNA (siRNA) targeted against a
(ascorbic acid) could effectively permeate and sustain the pres- signal protein transducer and activator of transcription. The
ence of vitamin C in the skin when compared with using only study found that the combination of curcumin and siRNA deliv-
a vitamin C solution. The study also showed that this delivery ered by cationic liposomes was more effective in reducing the
method could promote collagen synthesis by fibroblasts, which growth of skin cancer cells than either treatment alone.[34]
is essential for healthy skin.[33] Depending on the liposome’s composition and properties,
Alternatively, cationic (positively charged) liposomes, can be drug penetration can be enhanced or reduced through the skin.
used for targeting skin cancer cells. Anup Jose et al. conducted For example, liposomes composed of high levels of cholesterol,
a study to investigate a new method of treating skin cancer using or long-chain saturated fatty acids, can increase the penetration

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of drugs through the skin. Liposomes composed of short-chain PEVs. These vesicles can be applied to the skin in creams, gels,
saturated fatty acids, or unsaturated fatty acids, on the other or sprays and can help improve the efficacy of topical drugs by
hand, can reduce the penetration of drugs through the skin.[32] increasing their penetration through the skin. The choice of the
A study by Lueangarun et al. evaluated the efficacy and safety vesicular system depends on the drug properties, the desired
of a topical liposomal cream containing botulinum toxin type A therapeutic outcome, and the targeted skin layer.
(BTX-A) for treating primary axillary hyperhidrosis. The study
showed that the topical BTX-A liposomal cream effectively
reduced sweat production in the axillary area and was well- 3.2.1. Ethosomes
tolerated, with no serious adverse events.[35]
Despite the significant growth in liposomes, conventional lip- Ethosomes are a type of vesicular delivery system that are com-
osomes are not often considered a practical option for transder- posed of up to 50% v/v ethanol in their formulation, as shown in
mal drug delivery. This is because they cannot penetrate through Figure 2. Ethosomes have been found to improve skin penetra-
the deep layers of skin and instead tend to be retained in the SC, tion and increase drug accumulation in the skin when compared
due to their rigid structure.[26] with other vesicular delivery systems.[38] Previous research has
As a result, there has been growing interest in deformable lip- suggested that ethanol can partition the vesicle bilayers and
osomes, also known as flexible liposomes. They are characterized enhance their ability to penetrate skin cells.[39]
by their ability to change shape in response to external forces. They have been studied for use in various applications, includ-
The presence of more unsaturated fatty acids and the increased ing skincare and dermatology, wound healing, and the transder-
fluidity of the phospholipid bilayer give the liposomes their flex- mal delivery of drugs. Ethosomes exhibit negative zeta potential,
ibility. The increased fluidity allows the liposomes to easily which indicates better physical stability and higher permeation of
change shape in response to external stimuli, such as changes vesicles;[40] however, one of the potential drawbacks of using
in pressure or pH, making them a promising option for SDD. ethosomes is that the ethanol content may produce a dehydrating
A study by Wang et al. aimed to develop a flexible liposomal effect on the skin, causing dryness or discomfort. Additionally,
gel to treat psoriasis. The gel was loaded with all-trans retinoic ethanol may also disrupt the integrity of the skin’s lipid barrier,
acid (ATRA) and betamethasone, two drugs commonly used potentially reducing the effectiveness of the ethosomes in deliv-
to treat the skin condition. The study found that the liposomal ering the active compounds.[41] Other than ethanol, solvents such
gel was more effective in reducing psoriasis symptoms than as propylene glycol and glycerol can also be used to formulate
using ATRA or betamethasone alone. The liposomal gel also ethosomes. Incorporating these additional solvents can bring var-
improved the skin’s hydration level and elasticity.[36] ious benefits, such as enhancing the delivery and penetration of
Another study aimed to develop a deformable liposomal for- the active compounds into the skin. According to composition,
mulation using the surfactant Tween 20 for the delivery of epi- ethosomes can be divided into three categories: classical, binary,
gallocatechin gallate (EGCG), a compound with antineoplastic and transethosomes.[42]
properties, to treat skin cancer in a Caucasian population. The All three forms of ethosomes have a core of phospholipids,
results showed that as the amount of Tween 20 increased, the ethanol, water, and a charge-inducing agent as their primary
liposomes became more elastic, and the release of EGCG ingredients. However, classical ethosomes include a stabilizing
increased. The study also found that the liposomes could pene- agent, binary ethosomes incorporate an additional solvent such
trate and be localized within human dermal fibroblast and ker- as propylene glycol or other alcohol, and transethosomes include
atinocyte cells within 2 h. The study results suggest that the a surfactant or penetration enhancer.[42]
deformable liposomes may aid in drug penetration into dermal
cells and could help develop a controlled-release formulation for 3.2.2. Transethosomes
skin cancer treatment.[37]
The following section discusses different types of deformable/ Transethosomes, which are enhanced ethosomes with added
flexible liposomes or, in other words, PEVs. surfactants or permeation enhancers, offer improved flexibility
and skin penetration. This advancement is achieved through a
3.2. Penetration-Enhancing Vesicles (PEVs) formulation process that integrates ethanol or surfactants with
liposome preparations, enhancing compound permeability.[43]
PEVs are a type of deformable liposome specifically designed to Transethosomes have been used for antifungal and anti-
enhance the penetration of drugs through the skin. They are usu- inflammatory treatments, demonstrating significant improve-
ally composed of a mixture of lipids, surfactants, and other ingre- ments in drug permeation and therapeutic outcomes when
dients which can deliver a wide range of drugs, including compared with traditional methods.[44] Their effectiveness
hydrophilic and hydrophobic chemicals, for both transdermal extends to delivering antioxidants and anti-inflammatory com-
and topical applications.[3] pounds.[45] In addition, transethosomes can also be used to
Depending on the structure and composition of the vesicle, deliver vitamins and caffeine through the skin.[46] Their small
PEVs can improve SDD by four different mechanisms: modify- size, stability, and high drug-loading efficiency are advanta-
ing skin structure, enhancing skin permeability, increasing drug geous for sustained drug release.[47] In another example, trans-
solubility, and creating temporary passages through the skin.[11] ethosomes were used for the transdermal delivery of vitamin D,
Different methods, such as hot homogenization, sonication, with ongoing studies aimed at clinical validation and potential
extrusion, and emulsion diffusion, can be used to prepare FDA approval.[48]

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3.2.3. Proposomes 3.2.4. Glycerosomes

Proposomes, which are liposome-based carriers enhanced with Glycerolsomes are a type of liposome-based carrier system that
propylene glycol (PG), have been thoroughly researched for their incorporates glycerol as a key component. Glycerol is a versatile
potential to improve transdermal drug delivery. Propylene gly- solvent that can be used to solubilize lipids, drugs, and other mol-
col’s role is crucial as it solubilizes the lipids in the SC, leading ecules. In the context of liposome-based carrier systems, glycerol
to increased drug permeation through the skin. Moreover, PG is used to improve the stability and drug-loading capacity of the
has a synergistic effect with the skin’s own phospholipids, giving liposomes, as well as to enhance the skin penetration of drugs.
proposomes a distinctive edge in drug delivery applications. These carriers are similar to transethosomes and proposomes
Proposomes have shown better permeability when compared in that they enhance the skin permeation and delivery of drugs,
with traditional ointment-based treatments, attributable to the but instead use glycerol instead of ethanol or PG. This improves
specific amount of PG in the proposomes.[49] the penetration and encapsulation of drugs due to the soft and
The effectiveness of proposomes in drug permeation is influ- elastic nature of the vesicles and their increased size and stability.
enced by the lipophilicity of the loaded drug as well, as shown in These systems have been investigated for their potential to
Figure 3. Higher log P values enhance both permeation and improve SDD of drugs such as hydrocortisone, retinoids, cele-
entrapment, highlighting the role of a drug’s lipophilicity in coxib, and other lipophilic drugs, as well as hydrophilic drugs
its transdermal delivery via proposomes.[49] such as diclofenac sodium and paeoniflorin.[52]
Studies focusing on tofacitinib citrate, a drug used for skin Glycerolsomes were first proposed in 1980 as a means to avoid
conditions like psoriasis, atopic dermatitis, and alopecia, have systemic absorption after penetration of the dermis and epider-
shown that proposomes can significantly increase the drug’s skin mis. They can be prepared using various liposome techniques,
permeability by up to 11- fold, depending on the proposome com- such as the thin-film hydration and reverse-phase evaporation
position.[49] Further research involving a naringin-loaded propo- methods, they can be prepared at room temperature, and are suit-
somal gel has illustrated its efficacy in wound healing by able for incorporating heat-sensitive materials.[52,53] In 2012,
enhancing drug permeability and providing prolonged drug Manca et al. combined dipalmitoylphosphatidylcholine (DPPC)
release, tripling the quantity of drug released when compared with high concentrations of glycerine (10–30%) for the first time
with a naringin solution, which led to improved wound healing as glycerosomes, which achieved higher accumulation and trans-
over standard treatments.[50] Another study assessed the ability of dermal delivery of nonsteroidal antibiotics than conventional
proposomes to deliver various drugs with different physicochem- liposomes.[54]
ical profiles through the skin. The findings indicated entrapment Different phospholipids with varying transition temperatures
efficiencies between 42.9% and 52.7% and showed that the skin have been found to affect the efficiency of skin delivery. Yasmin
permeation enhancement ratio ranged from 1.4 to 4.0. Notably, et al. found that using synthetic phospholipids in glycerosomes
the enhancement in skin permeation was linearly related to the resulted in higher drug entrapment and better skin permeation
logP, molecular weight melting point of the drugs. The propo- than natural phospholipids.[53] The presence of glycerol in the
somes not only allowed for greater drug permeation than simple liposomes helps to improve the permeation of drugs, likely
solutions but were also safe for skin application. It was concluded due to its moisturizing properties, which increased the skin’s
that the effectiveness of SDD using proposomes depends on the hydration level.[55]
lipophilicity of the drug, with a clear positive relationship A study developed a novel glycosome carrier system contain-
between entrapment efficiency and the drug’s logP.[51] ing essential oils for transdermal delivery of the drug

Figure 3. Drug absorption in skin via proposomes is dependent on the lipophilicity of the loaded drug. Reprinted with permission.[49] Copyright, Elsevier
(License Number 5492870313399).

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paeoniflorin, which is used in the treatment of rheumatoid are frequently employed as nonionic surfactants in the prepara-
arthritis caused by synovium lesions. The glycerosomes were for- tion of niosomes.[60]
mulated using a uniform design, optimized to contain 5% phos- For example, a study aimed to investigate the potential of dif-
pholipid, 0.6% cholesterol, 10% glycerol, and 2% speranskia ferent PEVs (niosomes, proniosomes, ufosomes, and proufo-
tuberculata essential oil (STO) as a transdermal enhancer. The somes) to deliver the antibiotic roxithromycin for the
results showed that using STO-glycerosomes resulted in a treatment of acne vulgaris by targeting the dermis. Different
1.4- to 1.7-fold increase in transdermal flux and a 3.1-fold greater forms of roxithromycin (crystalline and amorphous) were encap-
accumulation of PF in the synovium than other vehicles. The sulated into the vesicles. The study found that PEVs containing
study concluded that STO-glycerosomes may be useful for treat- different forms of roxithromycin were successfully prepared and
ing rheumatoid arthritis.[52] characterized and had properties that were optimal for topical
delivery. The study also found that the vesicles were able to
3.2.5. Ufosomes deliver roxithromycin to the epidermis and dermis, while none
of the drugs were found in the receptor compartment. The study
Ufosomes, also known as unsaturated fatty acid vesicles, are a concluded that the niosomes were the leading formulation,
type of liposome made up of a phospholipid bilayer that includes the amorphous forms of roxithromycin had better topical
both unsaturated fatty acids (in their nonionized, neutral form) delivery than the crystalline form, and that targeted delivery of
and their ionized soaps (a negatively charged form). A specifically roxithromycin to the dermis where it is needed to combat
balanced ratio of these two types of fatty acids is crucial for main- Propionibacterium acnes was successful.[57]
taining the stability of the vesicle. The membrane structure of a Niosomes have been utilized in the treatment of a variety of
ufosome is more stable than that of a traditional liposome.[56] skin conditions, including skin cancer, psoriasis, eczema, fungal
The lipophilic nature of ufosomes allows for increased pene- infections, wound healing, and for cosmetic purposes, such as
tration of the skin when loaded with lipophilic drugs. hair loss and as a sunscreen. They have been sown to improve
Additionally, being composed of fatty acids, ufosomes can inter- the bioavailability, stability, and safety of drugs, as well as increase
act with the outermost layer of the skin, leading to improved bio- the duration of their effects on the skin.[60]
availability of hydrophilic drugs when applied topically.[56] A study by Eid et al. showed that incorporating terpene-rich
Ufosomes can be prepared using standard liposome preparation essential oils within niosomes can modify the niosome structure,
methods, for example, the hand-shaking method.[57] resulting in a higher drug penetration rate than the oil-free nio-
Ufosomes have the advantage of elongating drug release time somes when delivering felodipine.[61] Zhang et al. showed that
and because they consist of moderately priced fatty acids, ufo- the enhanced charge of niosomes created with sodium dodecyl
somes can be more economical relative to other lipid types. In sulfate increased the stability of the niosomes.[62]
addition, the high rigidity of the ufosomes membrane also Another study aimed to prepare niosomes as a transdermal
improves drug entrapment efficiency. Fatty acids are attributed delivery system of diacerein for osteoarthritis management.
to the extensive entrapment of drugs, as they are in the vesicles The study found that the formulation showed an entrapment effi-
with hydrophobic tails facing toward the interior. Greater entrap- ciency percentage of 95.63% and a particle size of 436.65 nm.
ment percentages of up to 99% were observed with an increase in The study also found the prepared vesicles showed enhanced
the drug to lipid ratio. skin permeation and retention when compared with a suspen-
A study aimed to investigate the potential of using ufosomes sion formulation of the drug. The study concluded that a trans-
as a delivery system for the antifungal agent clotrimazole. The dermal niosomal system was successfully prepared and evaluated
study found that ufosomes were able to entrap clotrimazole effec- using a central composite design, which could deliver diacerein
tively and improve its bioavailability when applied topically to efficiently and bypass the problems of delivering the drug via the
human skin. The study concluded that the use of ufosomes oral route.[59b]
improved the skin bioavailability of clotrimazole when compared For a cosmetic application, a study aimed to develop, charac-
with the marketed formulation.[56] terize, and optimize morin niosomes composed of nonionic sur-
factants and evaluate the in vitro UV protection and anti-aging
effectiveness of the product. The study concluded that the opti-
3.2.6. Niosomes
mized morin-loaded niosomes were stable, had extended-release
properties, and exhibited anti-aging activity including antityrosi-
Niosomes are a type of vesicle that are similar to liposomes. They
nase effects, antioxidant activity, and intracellular reactive oxygen
are composed of a closed bilayer vesicle made up of nonionic sur-
species (ROS) scavenging activity. Additionally, the study found
factants and cholesterol, as shown in Figure 2. Due to their
that the niosomes provided significant sun protection when com-
improved stability, niosomes are a better alternative to liposomes.[58]
pared with a cream formulation that contained only morin, sug-
The bilayer structure of niosomes allows them to mimic the
gesting that the product could be used in both pharmaceutical
natural structure of cell membranes, which enables them to pen-
and cosmetic products.[60]
etrate the skin and deliver drugs to the desired location.
Furthermore, niosomes can be formulated to target specific cells
in the skin, such as dermis, keratinocytes, or melanocytes, for 3.2.7. Bilosomes
enhanced efficacy. Niosomes can be prepared by standard lipo-
some preparation techniques such as the film hydration and Bilosomes are a unique SDD method that combines the proper-
ethanol-injection methods.[59] Families of spans, tweens, and brij ties of bile salts and niosomes. By incorporating bile salts, which

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are natural surfactants produced by the liver, into the membrane have been shown to have anti-inflammatory, antioxidant, and
of niosomes, bilosomes are created. Bile salts act as absorption anti-aging properties, and thus, have been investigated for the
enhancers, increasing the transport of drugs across biological treatment of skin conditions such as eczema, psoriasis, and rosa-
membranes by increasing the solubility of hydrophobic drugs cea. Flavonoids have also been used to protect the skin from UV
and making cell membranes more fluid. Bilosomes are commonly damage and to reduce the appearance of fine lines and wrin-
formulated using a combination of non-ionic surfactants, such as kles.[26] Common flavonoids delivered to the skin include: quer-
those in the span series, cholesterol, and bile salts. These chem- cetin, epicatechin, catechins, rutin, and kaempferol.
icals that are used to construct bilosomes are generally considered Flavosomes are a versatile delivery system that can either
safe and are both biocompatible and biodegradable. Bilosomes transport just flavonoids as the cargo or in combination with
have been successfully investigated for the transdermal/cutaneous other compounds, including anticancer drugs, enzymes, and
delivery of drugs, such as diacerein and tenoxicam.[63] growth factors. They can be used to treat a wide range of skin
A study evaluated the effectiveness of bilosomes for the topical conditions, as well as to deliver cosmeceuticals for cosmetic
treatment of acne. Using dapsone, which is a sulfone compound, purposes.[70]
the study showed that the bilosome system prepared with a com- For example, one study investigated the delivery of quercetin,
bination of Span 60, cholesterol (5:1), and 0.25 M sodium deoxy- a flavonoid with antioxidant and anti-inflammatory properties,
cholate bile salt was the best in terms of entrapment efficiency, using liposomes, lipid nanocapsules (LNCs), and smartCrystals.
in vitro release, and vesicle size. The bilosomes were spherical, did The study found that three different nanoformulations improved
not aggregate, and were able to deliver the drug through the layers of the delivery of quercetin, and the LNCs and smartCrystals were
rat skin more efficiently than an alcoholic solution of dapsone. The selected for testing on human skin. The study found that the
study also found that the bilosomes were safe and well-tolerated.[64] LNCs delivered quercetin to the epidermis, potentially treating
inflammatory skin disorders, while the smartCrystals were suit-
3.2.8. Cerosomes able for quercetin-based sunscreen products.[71]
Another study examined the use of flavosomes to act synergis-
Liposomes formulated using sphingolipids, such as ceramides, tically in the delivery other drugs. Zhang et al. found that using
are known as cerosomes. Sphingolipids are a class of lipid that flavosomes, that contained the flavonoids quercetin and dihydro-
play an important role in cell signaling, growth, cell death, and quercetin, enhanced the ability of meloxicam to penetrate deeper
maintaining membrane structure. Ceramides are the major com- into the layers of skin. Additionally, the presence of flavonoids
ponent of the skin’s natural lipids and are essential for the for- also added a synergetic anti-inflammatory effect to the meloxi-
mation of the skin barrier, which helps to keep the skin hydrated cam. This suggests that flavosomes have the potential as an alter-
and protect it from external damage. Incorporating ceramides in native method to oral delivery of nonsteroidal anti-inflammatory
SDD formulations can help to alter skin barrier function and drugs (NSAIDs) with enhanced local and systemic onset of action
enhance drug delivery.[10,65] and reduced gastrointestinal side effects.[26]
Cerosomes have been used in cosmetics and skincare to
improve skin barrier function and hydration, as well as reduce 3.3. Lipid NPs
the appearance of fine lines and wrinkles. Studies have also shown
that cerosomes can be used to repair damaged skin by replenish- Lipid nanoparticles (LNPs) are a type of colloidal carrier made
ing the SC lipid matrix and restoring its barrier properties. A study from ionizable lipids that are solid at ambient temperature.
by Strati et al. found that cerosomes composed of ceramides, stea- LNPs are small and can enter cells via endocytosis. Due to their
ric acid, and cholesterol can be stabilized at neutral pH by adding potential for delivering a wide range of drugs, including small
hydrogenated soybean phospholipids. The research also revealed a molecules, proteins, and nucleic acids, LNPs have been the focus
strong interaction between the cerosomes and the SC, as the of research and investment by major pharmaceutical companies,
ceramides in the cerosomes establish intermolecular hydrogen especially during the COVID-19 pandemic.[72] There are several
bonding networks. These findings suggest that cerosomes can types of LNPs, including: solid LNPs, nanostructured LNPs,
be used to repair damaged skin by replenishing the SC ’s lipid polymer–lipid hybrid LNPs, and nanoemulsions. Solid and nano-
matrix and restoring its barrier properties.[66] structured LNPS are the most used due to their stability and abil-
Additionally, research by Azarbayjani et al. found that cerosomes ity to be modified for targeted drug delivery.
can enhance the absorption of drugs through the skin, as seen with
diclofenac.[67] Albash et al. also found that PEGylated cerosomes 3.3.1. Solid Lipid NPs
loaded with fenticonazole nitrate improved skin permeation and
deposition of antifungal drugs.[68] Abdelgawad et al. loaded tazaro- A SLN is a type of NP made from lipids that have been melted
tene into cerosomes and found that while drug release was and then solidified. They offer a combination of benefits from
decreased, drug deposition in the skin was enhanced. When tested both liposomes and polymeric NPs but in a biodegradable form.
on psoriasis patients, they resulted in improved clinical outcomes.[69] Unlike liposomes, SLNs have a rigid lipid core, which provides
increased stability against coalescence, drug leakage, hydrolysis,
3.2.9. Flavosomes and particle growth. Additionally, SLNs have a high efficiency for
entrapping lipophilic drugs because they lack the aqueous core
Flavosomes, also known as flavonoid-based liposomes, are a fam- present in liposomes. This unique structure also enables more
ily of deformable liposomes that contain flavonoids. Flavonoids effective targeting of drugs and controlled drug release. They

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are superior to polymeric NPs because SLNs are prepared using size, high drug encapsulation efficiency, and good stability.
physiological lipids and do not need to be made with inorganic These properties allow the HA-NLCs to effectively deliver the
ingredients, making them less toxic and more biocompatible. drug to targeted areas and improve the effectiveness of the drug.
SLNs have been used for SDD applications, such as delivering For example, a study by Yue et al. shows that a specific type of
retinoids and steroids.[19] NLC called HA-bupivacaine/NLCs, which had a small particle
A study investigated using SLNs as a delivery system for vita- size, high drug encapsulation efficiency, and good stability, effec-
min A which utilized a specific combination of carrier materials tively improved the transdermal delivery and prolonged the anti-
(Gelucire 44/14 and cetyl alcohol). The study results indicated nociceptive effect of bupivacaine when compared with free
that the SLNs had a high encapsulation efficiency (90%) for vita- bupivacaine. These results suggest that HA-modified NLCs
min A, were stable, and effectively protected it from may be a useful platform for developing a sophisticated dermal
degradation.[73] delivery system for analgesic drugs.[76]
Another study examined the improved delivery of etodolac, an Another study by Prabahar et al. developed a novel SDD sys-
NSAID, by creating a topical formulation using SLNs. The tem for treating androgenic alopecia, by combining two different
researchers used a modified microemulsion technique to prepare approaches: physical and nanotechnological. Their design
the etodolac-encapsulated SLNs. It was found that the SLN-based utilizes NLC loaded with β-sitosterol, promoted as a natural treat-
gel enhanced the permeation of the drug through the skin and that ment for hair loss, which is then incorporated into chitosan-
the addition of lecithin played a key role in improving the perme- based MNs. The results showed that the steady-state flux of
ation rate. In vivo analysis showed that the SLN gel effectively NLC-MN was significantly higher than that of a regular NLC for-
reduced inflammation, starting from the third hour and continued mulation. The study also found that the NLC-MN delivery system
throughout the treatment period.[74] significantly enhanced hair growth in rats, reversing androgen-
Khan et al. researched the preparation of tacrolimus-loaded induced hair loss and promoting hair follicle dominance in the
SLNs that were formulated into a gel for improved topical use anagenic growth phase. Overall, the study concluded that the
in treating atopic dermatitis. The study found that sustained NLC-incorporated MNs have the potential to be an effective treat-
gel formulations released the drug slower than the original SLN ment for androgenic alopecia.[78]
form. However, both the SLNs and the gel ultimately led to the
same level of drug permeation, but the gel had superior retention
3.3.3. Polymer-Lipid Hybrid NPs
of the drug due to its stronger bioadhesive properties.[75]
In the treatment of acne, a recent study developed a topical gel
Polymer-lipid hybrid NPs (PLNs) comprise a polymer core cov-
containing isotretinoin (ITN) and alpha-TA in solid lipid NPs
ered by a lipid layer. These were developed based on the concept
(AE-SLN) to improve skin sensitivity and enhance treatment effi-
that combining liposomes, and polymeric NPs would be better
cacy. The AE-SLN was prepared using a microemulsion method
than using just pure lipids or polymers.[79] PLNs have been stud-
and evaluated for particle size, zeta potential, entrapment effi-
ied as a potential method for SDD. The polymer component can
ciency, drug release, skin irritation, and anti-acne activity in rats.
provide stability and controlled drug release, while the lipid com-
The study found that the gel had sustained drug release, was well-
ponent can help the NP target specific cells in the skin, such as
tolerated by the skin, and showed potent efficacy in the rat acne
keratinocytes. Additionally, the lipid component can help the NP
model. The results suggest that the AE-SLN gel has the potential
penetrate the skin barrier and reach the deeper layers of the skin.
as a nonirritant treatment for acne.[19]
A study developed a method for delivering Coenzyme Q10
(CoQ10) using monolithic PLNs as a promising treatment for
3.3.2. Nanostructured Lipid Nanocarrier psoriasis. The study concluded that the NPs were produced with
an encapsulation efficiency of 78.5% and that the PLNs released
NLCs are a type of lipid NP composed of a solid lipid core and a CoQ10 steadily and consistently for up to 3 days. The study also
surfactant coating. They are similar to SLNs but have a higher showed that when the formulation was used as a topical gel, it
level of solid lipids and lower surfactant content, resulting in demonstrated non-Newtonian rheological characteristics, and
a more stable and homogenous particle size. NLCs are used when it was applied topically to an imiquimod-induced psoriatic
in the pharmaceutical industry as drug delivery systems, as they mouse model, it produced a significant increase in CoQ10 effi-
can improve the bioavailability and stability of drugs and can be cacy when compared with other free CoQ10 gels. Therefore, the
used for various routes of administration, including oral, topical, study indicated that the CoQ10-loaded gel was effective as an in
and parenteral. NLCs can easily penetrate through skin and vivo application for treating psoriasis-like skin conditions.[80]
deliver drugs to the deeper layers, which is why they have been Another study investigated a new method for delivering clo-
studied for various skin conditions such as acne, psoriasis, and betasol propionate, a topical corticosteroid, using PLNs to treat
eczema. They can also have application in the delivery of vita- psoriasis. The study found that PLNs, made of lipids and an
mins, antioxidants, and other active ingredients in cosmetic amphiphilic copolymer, had 84.3% encapsulation efficiency
products. They are widely used in the cosmetic industry for skin and sustained release for 7 days when formulated into a topical
and hair care products. They are an effective delivery system for hydrogel. It also showed that PLNs improved cellular uptake
lipophilic chemicals such as lutein and clotrimazole, as well as and reduced skin damage and proliferation when applied to
hydrophilic drugs, such as enoxaparin.[76,77] mice with psoriasis-like inflammation. The study suggests that
Hyaluronic acid (HA) can be incorporated into NLCs, which PLNs have the potential for future clinical use in psoriasis
can be designed to have specific properties such as small particle treatment.[81]

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One important lipid polymer hybrid NP (LPN) application is delivery systems.[84] In addition, due to their ability to incorporate
gene delivery to the skin. A study found that a combination various substrates onto their surface, LCNPs have been used as
device of HA-based dissolving MN and LPNs could effectively targeted delivery systems.[86]
deliver miR-218 for treating alopecia. The device enhanced the The increased interest in using LCNPs in SDD is due to their
permeability of the skin’s SC and protected the miRNA from deg- ability to improve skin penetration, enhance drug absorption,
radation. The study found that the MN patches were more effec- protect drugs from degradation, enhance solubility, and mini-
tive in promoting hair growth than topical smear treatments and mize the toxicity of some administered drugs.[84] Several types
showed higher bioavailability of miR-218 in the dermis region. of LLCs can be formed depending on the type of lipid and sur-
The study established the combination device as a novel and factant used and their relative concentration, including cubo-
effective approach for localized transdermal miRNA delivery somes (cubic phase LLCs), hexosomes (hexagonal phase
to promote hair regrowth.[82] LLCs), lamellar phase LLCs (bilayer structure composed of lipids
and surfactants), reverse hexagonal phase LLCs (different struc-
3.3.4. Lyotropic Crystals NPs ture than hexosomes formed by self-assembly of lipids and sur-
factants), and columnar phase LLCs (cylindrical structure
Liquid crystals (LC) are a unique intermediate state of matter composed of lipids and surfactants).
exhibited by some compounds (i.e., mesogens) that combine The following section will discuss the most common LLCs
the properties of isotropic liquids, such as fluidity and the prop- studied for use in SDD. They are considered potential platforms
erties of anisotropic solid crystals, such as positional order and for SDD due to their unique properties, such as a high surface
orientation, thus having attributes of solids and liquids. Liquid area-to-volume ratios, the ability to encapsulate a wide range of
crystalline delivery systems have been studied for their enhance- drugs, the ability to sustain drug release, and low toxicity.
ment of colloidal stability, sustained release, flexible structure, and Cubosomes: Cubosomes are folded lipid bilayers curved in 3D
self-assembly. There are two types: thermotropic and lyotropic, space and have water channels within their structures (Figure 4).[87]
where the latter is often used for drug delivery applications.[83] They are formed from the dispersion of the cubic phase of LCs.
Lyotropic liquid crystals (LLC) are less toxic, with high perme- Their structure allows for enclosing different moieties such as
ability of the skin, and are known for protecting encapsulated hydrophilic (in the aqueous channel), lipophilic (in the lipid
drugs for longer duration. In addition, LLC can encapsulate bilayer), and amphiphilic drugs (inside the bilayer–water interface).
almost all types of drugs and macromolecules for oral and Due to their similar structure to epithelium cells, cubosomes can
SDD. However, the prepared LC phase has minimal application easily penetrate skin and mucosa.[88] Cubosomes are an example of
due to its high viscosity, which encourages liquid crystalline NPs how LCNPs can enhance topical delivery via endocytosis or mem-
or LCNPs; these can be prepared by dispersing LC in aqueous brane fusion. They have been studied as a potential platform for
media with mechanical or ultrasonic energy.[84] LCNPs offer SDD due to their unique properties, such as their high surface
advantages over LC, with lower viscosity, increased surface area, area-to-volume ratio, ability to encapsulate a wide range of drugs,
ability to provide sustained drug release, and their nanosize, and ability to sustain drug release.[89]
which allows for administration via the IV route.[84] Due to A recent study presented the development of a new method for
the biocompatibility of lipids, LCNPs have been used in deliver- delivering dexamethasone acetate, a corticosteroid, using cubo-
ing hydrophilic, hydrophobic, and amphiphilic drugs. In addi- somes (DA-Cub) and its subsequent gel formulation (DA-Cub
tion, cationic liquid crystalline NPs, or CLCNPs, have been gel) as a promising treatment for skin conditions. The study con-
studied for gene delivery applications[85] and in transdermal drug cluded that prepared DA-Cub had an encapsulation efficiency of

Figure 4. Schematic representation of cubosomes and their use in the delivery of an antimicrobial peptide into the skin. Reprinted with permission.[87]
Copyright, Elsevier (license Number 5493950032925).

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97.97  1.06%. The study also showed that DA-Cub and its gel like SLNs and NLCs. Generally, nanoemulsions have lower drug
had a sustained-release effect. In addition, the study found that loading capacity and reduced skin permeation potential when
the accumulation of DA-Cub and DA-Cub gel in rat skin in vitro compared with NLCs. However, when positively charged, nanoe-
increased significantly when compared with general gels and mulsions can serve as effective systems for SDD due to the pres-
commercial creams, which resulted in a significant increase ence of permeation enhancers in their structures, albeit at the risk
in intradermal retention. Furthermore, the study suggested that of potentially disturbing the skin layers and causing irritation.[94]
when compared with a commercial cream, DA-Cub provided a An example of the practical applications of nanoemulsions is a
higher penetration rate of the drug and better intradermal reten- recent study that developed sunflower oil-based nanoemulsion
tion. The study also suggested that DA-Cub and the DA-Cub gel formulations as sunscreens. These nanoemulsions exhibited
can make the cuticle thinner, change the structure of keratin, and higher sun protection factor values than traditional emulsions,
enlarge the intercellular space, thus promoting the penetration of primarily due to their smaller globule size, which allowed for
drugs. The study concluded that DA-Cub had a significant thera- more effective absorption of ultraviolet light. Therefore, these
peutic effect and is expected to become a new low-toxic and long- sunflower oil nanoemulsions could be considered more effective
acting preparation for treating skin conditions.[90] for sunscreen cosmetic use when compared with traditional
Another study investigated the use of cubosomes as a delivery emulsions.[95]
system for the antimicrobial peptide (AMP) LL-37 for treating In the medical realm, a specialized oil-in-water nanoemulsion
skin infections caused by bacteria, such as Staphylococcus aureus. known as NB-201 was formulated using pharmaceutically
Three different preparation protocols were used to produce AMP- approved ingredients including cationic and nonionic surfac-
containing cubosomes and were compared for their particle size, tants, ethanol as a humectant, a chelating agent, highly refined
size distribution, and release of LL-37. The study found that high soybean oil, and water. NB-201 was specifically designed for
loading of LL-37 into cubosomes resulted in the formation of the treatment of partial-thickness thermal burn wounds.
vesicles with no release of the peptide observed. The study also Remarkably, the topical application of NB-201 had a significant
found that LL-37 was fully protected against enzymatic attack when impact in attenuating the progression to full-thickness burn inju-
associated with the cubosomes, resulting in a bactericidal effect ries, when compared with silver sulfadiazine- and saline-treated
that was retained after enzyme exposure. The study concluded that burns. By day 21, both 20% and 40% NB-201 used on burned
cubosomes containing LL-37 prepared by preloading are promis- skin showed healing characteristics that were consistent with
ing for SDD applications and have a high potential for treating skin normal unburned skin, both to the naked eye and under histo-
infections caused by bacteria like Staphylococcus aureus.[87] pathological examination.[96]
Hexosomes: Hexosomes are particles made up of inverted
hexagonal LC phases suspended in a water-based medium.
Their unique structure makes them a potential option for SDD.
4. Inorganic Nanocarriers
Drugs can be placed within the aqueous compartment of the hex- Inorganic NPs, made of gold, iron, silver, molybdenum, and sili-
asomes or attached to the lipid components outside the water cas, are also being explored as potential carriers for SDD. Carbon
rods. Hexosomes offer improved solubility for drugs that are dif- nanomaterials, including nanotubes and graphene, have also
ficult to dissolve and enable effective delivery of therapeutic pep- been used for SDDs, such as anticancer agents and photosensi-
tides and proteins through oral, skin, and injection routes.[91] tizers, into, and through, the skin.
A recent study investigated the use of hexosomes for SDD.
The results showed that hexosomes have the potential for the
4.1. Metal NPs
delivery the antifungal drug ketoconazole. Their structure was
determined to be hexagonal with a median particle size of 4.1.1. Gold NPs (AuNPs)
107  20 nm and a positive zeta potential, which enhanced its
interaction with the skin and mucous membranes. Additionally, Gold NPs (AuNP) show great potential, due to their customizable
the hexosomes were found to be both physically and chemically size[97,98] and because they are nondeformable when compared
stable and exhibited mesophasic thermal reversibility, which with the other nonmetallic NPs.[97] Several studies reported
make them ideal for SDD.[92] AuNP applications in cosmetics,[20b] anti-inflammation,[99] and
Another study by AlZuhairi et al. evaluated the effectiveness of cancer treatment.[98,100] Gupta et al. developed AuNPs that were
a newly developed petrolatum-LC ointment for SDD. The study found to successfully aid protein delivery into the skin without
assessed the physical and chemical properties of the ointment, as attaching to the AuNP itself.[97] In addition, the AuNPs were
well as its ability to release medication and enhance skin pene- reported to pass through areas of thick skin, such as the palms,
tration. The results showed that novel petrolatum-LC formula- easily.[101] Nonetheless, the long-term toxicity of AuNPs via SDD
tions are biocompatible, form hexosomes, and they are more has not been well studied, which needs further investigation
effective in improving skin permeability and drug concentration before clinical trials.
when compared with commercial petrolatum.[93]
4.1.2. Silver NPs (AgNPs)
3.3.5. Nanoemulsions
Silver NPs (AgNPs) have been examined as a disinfection agent
Nanoemulsions are LNCs with liquid cores that have distinct for wound healing for many years.[102] An AgNP-loaded hydrogel
advantages when compared with other types of lipid nanocarriers has shown outstanding results for wound healing when

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compared with existing commercial gels.[20a] However, the agents and in facilitating wound healing.[110] Advances in NP
AgNPs were reported to have toxicity when silver ions were engineering, such as controlling their size and shape through
released.[103] methods like microemulsion and reverse micelle synthesis, have
To study AgNPs’ permeability through both animal and broadened their application in industry and medicine.[111]
human skin, Kraeling et al. selected commercially available CuNPs, especially copper silicate hollow microspheres incorpo-
20 nm AgNPs and tested them using in vitro flow-through diffu- rated into bioactive scaffolds, are demonstrating their dual poten-
sion devices. The results showed that most AgNPs were trapped tial in targeting melanoma and supporting skin repair. Other
within SC, while very few reached the epidermis and dermis. In innovations include Cu2S NPs and Cu-MOF NPs, which, when
addition, the surface charges of AgNPs did not affect their per- combined with hydrogels, offer controlled drug release and min-
meability significantly.[104] imized toxicity, thus showing promise in both tumor suppres-
Another study investigated the possible skin penetration path- sion and chronic wound management.[110]
ways, namely, trans follicular and intercellular passages. It was Additionally, copper oxide NPs, particularly those loaded with
shown that AgNPs permeated through the intercellular pathway, cucumber extracts, are enhancing dermatological treatment,
apart from the transfollicular pathway. In addition, it was found while copper-infused antiviral nanofibers have contributed to
that the different shapes of AgNPs may exhibit different antimi- improved personal protective equipment against viruses like
crobial activities and skin penetration capabilities. The findings SARS-CoV-2.[112] A pivotal study by Ramazan et al. capitalized
added new knowledge to SDD using NPs, as most studies were on CuNPs and a copper quercetin complex for creating
focused on the size-dependent skin penetration of NPs via trans- sustained-release PCL NPs, which exhibited superior stability,
follicular pathways. Interestingly, the study found that size and effective drug delivery, and robust antibacterial properties, while
shape are the two critical factors governing the NPs for transder- proving to be gentle on the skin and effective in rat models for
mal drug delivery, consistent with other previous findings.[105] treating skin infections.[111]

4.1.3. Iron NPs (FeNPs) 4.1.6. Cerium NPs (CeO2-NPs)

Superparamagnetic iron-oxide NPs (SPIONs) have been studied for Cerium oxide NPs (CeO2-NPs) can mimic antioxidants, thereby
transdermal delivery in recent years, using an external magnetic field controlling ROS levels. They can act as oxidants in the acidic
as a physical enhancement mechanism. Rao et al. showed that an environments of cancer cells. In neutral pH systems, they
anticancer drug, epirubicin, when loaded onto SPIONs, could effec- protect healthy cells. The NPs’ redox flexibility comes from a
tively penetrate human skin and release the chemotherapy agent.[106] self-regenerating cerium-ion cycle.[113]
It was shown that the SPIONs permeated deep into the skin via the Recent studies have explored CeO2 NPs to target melanoma
follicular pathways, with the driving force of an external magnetic cells. These cancerous skin cells have higher lactase levels, mak-
field. Afterward, the drug was released, at an acidic pH commonly ing them more susceptible to CeO2 NPs. The NPs can disrupt
found in tumor tissue. In vitro, cytotoxicity testing showed that the mitochondria and increase ROS in the cancer cells, which can
SPIONs were compatible with human keratinocytes.[107] lead to cell damage and trigger apoptosis through cytochrome
c and caspases.[114]
4.1.4. Molybdenum NPs (MoNPs) CeO2-NPs also inhibit myofibroblast development, which can
halt cancer growth. Commercial CeO2 NPs have been used to kill
Molybdenum disulfide is a transition-metal dichalcogenide, with melanoma cells from in vitro studies. Thus, CeO2 NPs are a
a layered structure weakly bound by Van der Waals forces. It has potential treatment for skin cancer, especially melanoma. They
an ultrahigh specific surface area and has been extensively studied also show promise in radioprotection and wound healing.
for biological applications. Additionally, as a thermal-sensitive However, more animal studies are needed to confirm their safety
material, the release of encapsulated drug molecules can be and effectiveness.[113]
achieved using near-infrared irradiation. However, their high tox-
icity limits their application in SDD. To this end, transdermal drug 4.2. Silica NPs
delivery using molybdenum disulfide appears interesting, para-
doxically, because the NPs are too big to penetrate the skin.[108] Silica NPs, specifically mesoporous silica NPs (MSNPs), have
Zhang et al. modified the surfaces of molybdenum disulfide become a promising novel topical delivery system. The MSNPs
NPs using cationic hydroxyethyl cellulose.[108] The NPs had an have the advantages of having a high surface area and highly
average diameter of more than 300 nm, which limited their skin ordered pore network with high thermal stability and biocompat-
absorption. With near-infrared stimulation, the NPs increased the ibility.[115] The favorable characteristics enabled the delivery of
permeation into the skin of the drug atenolol. Similarly, others fragile drugs such as siRNAs through the membrane. MSNPs
also showed that poly-(acrylic acid)-modified NPs enhanced the have been loaded with various drugs for transdermal drug deliv-
skin permeation of atenolol with thermal stimulation.[109] ery, such as colchicine,[21] 5-fluorouracil,[116b] quercetin,[117]
methotrexate,[118] insulin,[119] and lidocaine.[120] Lio et al. demon-
4.1.5. Copper NPs (CuNPs) strated novel siRNA SDD using MSNPs for treating skin can-
cer.[121] In addition to MSNPs, the newly designed thiolated
Over the past decade, copper nanoparticles (CuNPs) have silica NPs have been reported to penetrate the skin via hair fol-
become integral in melanoma treatment, serving as antibacterial licles, allowing targeted drug delivery to the desired region.[116a]

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4.3. Carbon-Based Nanocarriers LP-ND complexes offer an alternative to current sunscreen

formulations.[131]
Carbon nanomaterials, mainly nanotubes and graphene, are
promising drug nanocarriers with unique physicochemical prop- 4.3.3. Fullerene
erties, such as large surface-area-to-volume ratios, high thermal
stability, high carrier capacity, and feasible incorporation of both The most prevalent fullerene type is fullerene C60. It is composed
hydrophilic and hydrophobic substances.[122] Furthermore, the of 60 carbons in a highly symmetrical truncated icosahedron
surface of carbon nanomaterials can be modified with targeting shape.[132] C60 has particular importance in SDD and cosmetics
moieties such as folic acid and antibodies.[122] In addition, carbon due to its antioxidant effect and its ability to interact with epider-
nanomaterials have been used as theranostics, which combine mal keratinocytes. It can be used in moisturizers, as an anti-
therapeutic and early diagnostics, particularly in cancer treat- inflammatory, it can provide cytoprotective UVB inhibition,
ment.[123] However, despite the great interest in carbon nanoma- act as a barrier-repair agent and hair growth stimulator, and
terials, their use is limited due to their debatable safety and very as an antimelanogenesis agent.[22b] Fullerenes have shown lim-
low solubility.[124] ited efficacy in peptide delivery.[22b] Despite this, the penetration
capability of C60 NPs, particularly those under 10 nm, has been
documented to reach the dermis and accumulate within hair
4.3.1. Carbon Nanotubes (CNT)
follicles.[132]
A study investigated the use of a fullerene-loaded nanoemul-
All CNTs have a typical cylindrical shape that can be open or
sion as a potential protective and regenerative agent against oxi-
closed on each end.[125] They have gained particular importance
dative stress-induced collagen breakdown in human skin. The
in SDD due to their ability to penetrate the skin with high chem-
study found that using the fullerene nanoemulsion for 28 days
ical and thermal stability, because they are lightweight and have a
significantly increased the collagen score and improved skin
large loading capacity.[22a] CNTs have been studied for SDD for
hydration. Additionally, in vitro safety evaluation showed that
small-molecular drugs, peptides, and nucleic acids.[126,127]
the fullerene nanoemulsion was not toxic to fibroblast cells.
A study has shown that a hybrid nanocarrier was able to facil-
Overall, the study suggested that the fullerene nanoemulsion
itate SDD using low-water-soluble ketoprofen (KP) loaded onto
may have the potential as a cosmeceutical product for protecting
functionalized multiwalled carbon nanotubes (f-MWCNTs)
collagen from breakdown.[133]
which were prepared by a single-step injection technique. The
Additionally, the application of fullerene-loaded nanoemul-
study found that the f-MWCNTs composite ethosomes formula-
sions has demonstrated positive outcomes in protecting against
tion had a sustained release effect, faster and deeper penetration
collagen breakdown due to oxidative stress, with significant
of the skin, and an improved pharmacokinetic profile when com-
improvements in collagen levels and skin hydration. Such find-
pared with commercial gels. Overall, the study results suggested
ings bolster the cosmeceutical potential of fullerene, indicating
that the f-MWCNTs composite ethosomes are a promising SDD
its capacity to act as both a protective and regenerative agent in
system.[128]
human skin without exhibiting cytotoxicity to fibroblast cells.[133]

4.3.2. Nanodiamonds 4.3.4. Graphene

Compared with other carbon nanomaterials, carbon nanodia- Graphene is a 2D honeycomb lattice composed of a single layer
monds (CNDs) are the least toxic. However, only a few studies of carbon atoms. It is known for its modifiable surface area, good
have demonstrated the SDD application of CNDs. Namdar et al. biocompatibility, and safety profile. In addition, graphene’s large
exclusively discussed the skin application of CNDs.[129] Wu et al. surface area enables efficient drug loading via adsorption or
showed the UV protective effect of CNDs in mice against UV-B chemical functionalization.[134] Graphene-based nanocarriers
radiation.[22c] Lim et al. demonstrated that fluorescein- (GBN) have been found to enhance the stability, bioavailability,
conjugated CNDs remain on the SC and have no diffusion to and photodynamic efficiency of photosensitizer molecules and
deeper layers even after 48 h of skin exposure. They also showed exhibit properties of electron sinks for enhanced visible light
that carboxylic CNDs could be loaded with a high quantity of photodynamic activity.[135] Additionally, due to its intrinsic
drug and that they enhanced drug in vitro permeation, improved near-infrared absorption properties, GBNs can be designed to
drug photostability, and showed synergistic antioxidant activity combine both photodynamic and photothermal therapies for
with eugenol.[130] optimal therapeutic effects. Compared with other nanocarriers,
A recent study investigated the use of lignin-poly (ethylene gly- GBNs have a much higher drug-loading capacity and can be tar-
col) (LP) nanodiamond (LP-ND) complexes as a natural-based geted to specific cells to deliver photosensitizers in photodynamic
alternative to current sunscreen products. They found that the therapy.[134]
LP-ND complexes had favorable UV filtration properties, The integration of graphene with organic polymers can
enhanced photostability, and had uniform dispersion in water improve material function, such as its mechanical, thermal,
and in a cream formulation. The LP-ND complexes were also and rheological properties.[134] For example, it has been shown
found to have enhanced synergistic effects when used in combi- that incorporating graphene into MNs enhanced the MNs’ mois-
nation with commercial sunscreens, which resulted in an ture resistance and the overall transdermal delivery of a chemo-
increased sun protection factor (SPF). The study concluded that therapeutic drug.[136]

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Another study presented a new method of delivering a drug, One notable study explored a topical liposomal formulations’
docetaxel, and a tryptophan derivative, 1-methyl-D-tryptophan, to efficacy for treating cutaneous leishmaniasis (NCT01050777).
skin tumors using heparin-modified graphene oxide nanosheets Liposomes were utilized to topically deliver meglumine anti-
(D-1/GH). The study found that D-1/GH can effectively perme- moniate, an injectable drug. Another study investigated the
ate the skin, infiltrate tumors, and then be transported to deeper potential of a T4N5 liposome lotion in preventing actinic kerato-
tumors via blood and lymphatic vessels. D-1/GH also enhanced ses, a precancerous condition, in patients with xeroderma pig-
the therapeutic effect of chemotherapy and photothermal mentosum (NCT00002811). This liposomal formulation
therapy, and it was able to recruit immune cells to suppress contained an enzyme involved in DNA repair after ultraviolet
abscopal tumors and lung metastases. Additionally, the study radiation exposure.
suggested a novel permeation mode for improving antitumor Additional clinical trials included the formulation and clinical
efficacy and boosting immune response while avoiding systemic evaluation of ethosomes and liposomes containing anthralin for
distribution.[137] psoriasis treatment (NCT03348462), the use of ethosomes for
retinyl palmitate delivery in acne vulgaris (NCT04080869), and
an examination of topical silver NPs for their antimicrobial activ-
ity against foot fungal and bacterial infections (NCT03752424).
5. Clinical Trials of Nanocarriers in Skin Delivery One study investigated the use of SLN loaded with oxiconazole
nitrate gel for the treatment of tinea (NCT03823040) versus the
Over the years, there has been a significant increase in the num- marketed cream Tinox. The entrapment efficiency and particle
ber of clinical trials that have explored nanocarriers for SDD. size of these NPs were found to be significantly influenced by
This less-known field has gradually gained attention as studies the concentration of the lipids and surfactants. Differential scan-
continue to demonstrate nanocarriers’ potential advantages in ning calorimetry results indicated reduced drug crystallinity and
enhancing drug delivery, improving patient compliance, and potential drug–lipid interaction. The optimized gel formulation
minimizing side effects. Therefore, a timely review of the avail- containing these SLNs demonstrated satisfactory physical char-
able clinical data is imperative to ensure that nanocarrier tech- acteristics, sustained in vitro drug release, and adequate skin per-
nology is optimally harnessed to improve patient outcomes. meation. Notably, the gel exhibited a high bioadhesive force,
We searched the clinicaltrials.gov database to identify clinical potentially prolonging the drug’s effect on the infected skin.
trials that utilized nanocarriers for topical and transdermal drug The drug’s release mechanism from the gel combined diffusion
delivery. We focused on lipid and inorganic nanocarriers, using a and polymer matrix erosion. The newly developed oxiconazole
comprehensive list of keywords, as described in the Literature nitrate SLNs represent a promising formulation for the treat-
Review Method section. ment of tinea fungal infection.
In our research, we refined our search to specifically focus on A study on diabetic wound ulcers (NCT04834245) found that a
studies related to SDD. Consequently, we set aside studies con- dressing made of hydrogel nanosilver was noted to enhance
cerning wound healing, burns, or those employing devices like wound healing by expediting re-epithelialization and wound con-
MNs, placing them in a separate category. We did not apply any traction, as indicated by a faster decrease in wound size. The
date restrictions to our search. The search yielded eight studies, dressings are cost-effective due to reduced hospital stays.
as shown in Table 2. The clinical trials on treating wounds Additionally, no adverse effects were observed in the group
with nanocarriers are listed separately in S1, Supporting treated with this dressing, suggesting its superiority in managing
Information. In addition, the drugs and their clinical applications chronic wounds. However, further extensive studies are neces-
covered in this review are listed in S2, Supporting Information. sary to investigate these observed effects. Given these findings,
Among the trials, diverse nanocarrier systems were investi- the hydrogel nanosilver dressing appears to be a safe and an
gated, including liposomes, ethosomes, SLNs, and silver effective supplementary treatment for diabetic foot ulcers.
NPs. Each study focused on different dermatological conditions Lipid-based nanocarriers like liposomes and SLN in skin deliv-
and aimed to assess the effectiveness of nanocarriers in improv- ery are favored due to their biocompatibility and drug encapsu-
ing SDD. lation versatility. However, inorganic nanocarriers have issues

Table 2. Clinical trials for skin topical and transdermal drug delivery using nanocarriers (C: Completed, NM: not Mentioned, SLN: solid Lipid
Nanoparticles, T4N5: T4 Endonuclease 5).

Nanocarrier Preparation Drug Phases Conditions Size NCT Number

Liposomes NM Meglumine antimoniate OR Paromomycin Phase 0; C Cutaneous Leishmaniasis 30 NCT01050777
Liposomes NM T4N5 Phase 3 Precancerous Condition 30 NCT00002811
Liposomes NM T4N5 Phase 2; C Actinic keratosis, Basal cell carcinoma, 100 NCT00089180
Squamous cell carcinoma
Ethosomes Ethanol injection Retinyl palmitate OR tretinoin Phase 2; C Facial acne vulgaris 20 NCT04080869
SLN Solvent evaporation Oxiconazole Phase 1; C Tinea 28 NCT03823040
Silver NPs Reduction reaction Silver NPs Phase 1; C Foot fungal and bacterial Infection 30 NCT03752424
Silver nitrate NPs NM Silver NPs Phase 2; C Umbilical Granuloma 176 NCT04248101

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regarding their potential toxicity and compatibility, which ham- Supporting Information
per their clinical progress.[17,27] Complex SDD systems also pres-
Supporting Information is available from the Wiley Online Library or from
ent significant hurdles. Attempts to improve the penetration of
the author.
drugs through skin frequently come with the potential drawback
of causing skin irritation. Balancing efficacy with safety is there-
fore critical in advancing nanocarrier use.[17]
Acknowledgements
The adoption of nanocarriers in SDD has seen incremental
progress. Challenges include navigating the skin barrier effi- L.A. is a recipient of the Deanship of Scientific Research, King Saud
ciently, establishing safety profiles, scaling production, and clari- University, Saudi Arabia.
Open access publishing facilitated by The University of Sydney, as part
fying regulatory pathways. The effectiveness of the Pfizer
of the Wiley - The University of Sydney agreement via the Council of
COVID-19 vaccine, which used lipid NPs as a delivery mecha- Australian University Librarians.
nism, has brought significant attention to the potential of this
method. Its widespread acceptance and success have established
a model likely to encourage more clinical trials and adoption in Conflict of Interest
the future for SDD.[72a]
The authors declare no conflict of interest.

6. Outlook
Keywords
As research progresses on nanocarriers for SDD, efforts are
directed toward bridging the gap between laboratory innovations drug delivery, formulations, nanocarriers, nanoparticles, skin, topical,
transdermal
and clinical application. Future developments aim to refine nano-
carriers, enabling targeted therapies that minimize side effects. Received: January 4, 2024
There’s a growing emphasis on developing “smart” nanocarriers Revised: March 14, 2024
capable of responding to stimuli like pH changes or skin Published online:
enzymes, thereby releasing therapeutic agents precisely where,
and when, needed.
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Lamyaa Albakr is currently pursuing her Ph.D. at the University of Sydney, specializing in the development of microneedle-
based transdermal delivery systems for novel antiviral drugs. Her research emphasis includes the chemical synthesis and
fabrication of microneedles using three-dimensional printing with photocurable polymers. She earned her bachelor (2016) and
master of science (2019) degrees in pharmaceutical sciences from King Saud University, graduating with honors.
Hongyuan Du received his honors bachelor of science degree in biological sciences from the University
of Toronto, Canda, in 2020. Afterwards, he continued his postgraduate education at Tongji Medical
College, Huazhong University of Science and Technology in China. Transitioning from years of practical
experience in stem-cell research to studying novel post-translational modifications of histones and
proteins, he values the process of discovery and the opportunity to expand his scientific horizons.

Xiyuan Zhang received her master of philosophy degree from the School of Pharmacy, Faculty of
Medicine and Health, University of Sydney in 2023. During her 2-year study, she studied recombinant
proteins and the expression of human leukemia inhibitory factor in yeast cells of Pichia Pastoris. In
addition, she also contributed to several projects on polymeric microneedles and solid dispersions to
deliver molecules with low solubility. Currently she is working in regulatory affairs in Aucta
Pharmaceuticals in China.

Himanshu Kathuria earned his Ph.D. from the National University of Singapore in 2018. He is currently
the technology manager and cofounder of Nusmetics Pte. Ltd in Singapore. He is an active researcher,
developing drug delivery technology for better healthcare and general well-being. His broad research
interests are drug delivery, microneedles, formulation, nanomedicine, microfabrication, 3D printing, and
nonpharmaceutical interventions. He has authored 34 peer-reviewed journal articles in leading journals,
and a book chapter, accumulating 1092 citations and H-index of 16 on Google Scholar. He has filled one
patent on microneedle devices.

Ahmad Fahmi Anwar Fadzil received his bachelor of pharmacy degree from University of Sydney in 2020.
He is currently serving as the pharmacist in charge at Chemist Warehouse Fyshwick in Australia.
Furthermore, he holds the position of intern coordinator in the state of the ACT for Chemist Warehouse.
In addition to his pharmacy duties, he is passionate about integrating 3D printing technology into
pharmacy practice to enhance patient outcomes. In 2022, he published a review paper, titled recent
progress in three-dimensionally printed dosage forms from a pharmacist perspective.

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Nial Wheate completed a bachelor of science (1998) and Ph.D. (2002) through the University of New
South Wales (UNSW). He was also awarded a doctor of science (2020) and master of business
administration (2021) from the University of Sydney (USYD). As a medicinal and pharmaceutical
chemist, Nial has held research and teaching positions at UNSW, Western Sydney University, the
University of Strathclyde, and USYD. His research is focused on advanced drug delivery methods and
pharmaceutical formulation, with a particular interest in macrocycles and nanoparticles.

Lifeng Kang is a senior lecturer in the School of Pharmacy, The University of Sydney, Australia. He
studies microfabrication and 3D printing technologies for drug delivery and tissue engineering. He has
published 77 peer-reviewed journal articles in this field, with 60 of them as the first or corresponding
author, accumulating a total of 3764 citations and an H-index of 35 on Google Scholar. Dr. Kang has
filed 10 patents, with 5 of them granted and 3 licensed. He is recognized as one of the world top 2%
scholars 2022–23, as determined by Stanford University.

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