Advances in polymeric nano-delivery systems targeting hair follicles for the treatment of acne

Abstract

Acne is a common chronic inflammatory disorder of the sebaceous gland in the hair follicle. Commonly used external medications cause skin irritation, and the transdermal capacity is weak, making it difficult to penetrate the cuticle skin barrier. Hair follicles can aid in the breakdown of this barrier. As nanomaterials progress, polymer-based nanocarriers are routinely used for hair follicle drug delivery to treat acne and other skin issues. Based on the physiological and anatomical characteristics of hair follicles, this paper discusses factors affecting hair follicle delivery by polymer nanocarriers, summarizes the common combination technology to improve the targeting of hair follicles by carriers, and finally reviews the most recent research progress of different polymer nanodrug-delivery systems for the treatment of acne by targeting hair follicles.

Keywords:

• Acne
• hair follicle administration
• polymeric nano-delivery systems
• targeted drug delivery
• polymer nanoparticle
• polymer micelle
• nanogel
• dendritic polymer

1. Introduction

Acne, as a common disease, has been listed as the eighth most prevalent communicable disease worldwide. It is a chronic inflammatory skin disease that involves the pilosebaceous unit. The clinical manifestations are characterized by multifocal lesions such as comedones, papules, cysts, nodules, and pustules, with the highest incidence in adolescents (Szepietowska et al., 2023). Studies have shown that acne causes certain damage to the patient’s facial skin, and the prognosis leaves various scars, making patients emotionally anxious, irritable, and inferior, thereby affecting their daily life and social activities (Dayal et al., 2020; Otlewska et al., 2020).

Early management of acne is crucial for acne patients, and the choice of treatment drugs is based on the severity of acne. Retinoids, antibiotics, and hormones are commonly used drugs in the topical or systemic treatment of acne (Oge’ et al., 2019; Eichenfield et al., 2021). Systemic treatment has better clinical efficacy, but it also has more severe adverse reactions, such as gastrointestinal discomfort, liver toxicity, and fetal malformations (Tolino et al., 2020; Kemeriz et al., 2021; Villani et al., 2022). Therefore, topical treatment is more suitable for patients with mild to moderate acne. However, although topical delivery of drugs to the skin can avoid systemic toxic side effects and is the main route of drug penetration, skin topical delivery poses a challenge due to the presence of the stratum corneum, which hinders the penetration of topical drugs. Therefore, the key to skin topical delivery is how to improve the bioavailability of topical drugs.

According to research, drugs enter the systemic circulation through the skin in two ways: the epidermal (intercellular and intracellular) pathway and the hair follicle accessory pathway (hair follicle, sebaceous glands, sweat glands) (Costa et al., 2021). Topical drug delivery through the epidermis has received more attention compared with the hair follicle appendicular route, mainly because the hair follicle only accounts for about 0.1% of the skin surface area (Kassan et al., 1996), which results in the hair follicle appendicular route being largely ignored by researchers.

There’s no denying that hair follicles have enormous potential as a source of topical skin treatments. On the one hand, the presence of hair follicles directly breaks down the keratin barrier, allowing drugs to enter the skin, particularly water-soluble drugs. The epidermal pathway is less effective than the hair follicle accessory pathway because it is more difficult to penetrate the lipid-rich stratum corneum. On the other hand, the hair follicles invaginated deep into the dermis significantly increase the actual surface area of the hair follicle, allowing it to play a role in drug storage to some extent (Blume-Peytavi & Vogt, 2011). Therefore, hair follicles are regarded as one of the most important routes of topical drug delivery and play an important role in drug diffusion. Furthermore, hair follicles are thought to be unique targets for topical nano-delivery in the treatment of follicle-derived diseases like acne and androgenic alopecia.

Nanotechnology has steadily become a research hotspot in the field of drug delivery due to the continuous development of nanomedicine technology. Drugs can be synthesized into nanoscale particles utilizing nanotechnology to improve drug water solubility (Mehan et al., 2022; Ratan et al., 2023), drug targeting, and drug release speed, thereby improving therapeutic impact and preventing side effects. Common nanodrug delivery systems include colloidal nanocarriers, lipid nanocarriers, polymer nanocarriers, etc. Colloidal nanocarriers such as microemulsion, nano-emulsion, and among others, mediate percutaneous drug delivery by increasing drug solubility, allowing it to reach the intercellular space around the stratum corneum of the skin, allowing it to continue to penetrate into the deep tissues of the skin, or themselves having a certain osmotic effect, reversible transient destruction of lipid bilayer structure, thereby enhancing drug delivery (Liu et al., 2019; Xu et al., 2022). Lipid nano-systems, such as solid lipid nanoparticles and nanostructured lipid carriers, can be freed from liposomes and reach the stratum corneum by fuzing with stratum corneum lipids due to their high lipophilicity. Modified liposomes, such as transfersomes and ethosomes, can enter the stratum corneum and convey medications into the active epidermis due to their particle size and structure, whereas regular phospholipid liposomes struggle to penetrate the entire stratum corneum due to insufficient membrane fluidity (Kalave et al., 2021; Liang & Zhang, 2021). Polymer nanocarriers, such as polymer nanoparticles and polymer nano-micelles, have a hard structure and a low deformation ability, making them difficult to completely enter the stratum corneum (Ushirobira et al., 2020; Al Mahrooqi et al., 2021). Studies have shown that polymer nanocarriers enter the deeper layers of the skin mainly through appendage pathways such as hair follicles and act as reservoirs to release drugs (Kahraman et al., 2017). Nanogels, in addition to enhancing skin moisture (Zhu et al., 2020) and modulating the fluidity of the stratum corneum lipid bilayer, have a profound effect on hair follicle aggregation, allowing nanogels with small particle sizes to penetrate deep into hair follicles (Sahle, Gerecke, et al., 2017). Different nanodrug delivery systems have different mechanisms of promoting permeability, and polymer-based nanodrug delivery carriers are more suitable for delivering drugs through the hair follicle pathway to achieve the efficacy of treating acne.

2. Structure of hair follicle

Hair follicles are tiny organs with complex three-dimensional structure with periodic activities, run through the skin’s epidermis and dermis and are surrounded by various cell populations, particularly those related to the immune system, such as antigen presenting cells and mast cells, which regulate various biochemical, immune, and metabolic activities (Martel et al., 2023).

It is made up of a constant top component and a constantly circulating bottom part, with the constant part being impervious to apoptosis and regeneration in general. The consistent part from top to bottom in terms of spatial organization is the infundibulum, isthmus, and bulge (Welle, 2023).

The infundibulum stretches from the skin’s surface to the sebaceous gland and is divided into two portions. The upper infundibulum is the shoulder infundibulum with epithelial cells that are continuous with the keratinized epidermis and are covered by the impervious cuticle, whereas the lower infundibulum has the inner epidermis of the funnel invaginate, which not only allows drugs to enter the hair follicle but also provides an additional absorption area and increases skin surface area. As a result, the infundibular region of the hair follicle is one of the most commonly used locations for topical drug delivery in the hair follicle.

The isthmus extends from the aperture of the sebaceous gland to the protuberance. The sebaceous glands of the isthmus are the only whole-plasma secretory glands in the human body, with secretions made up entirely of gland cells (Shamloul & Khachemoune, 2021). As exocrine glands, their secretory products must be transported to specified locations outside of the glands via excretory channels. As a result, excretory ducts connect the sebaceous glands to the hair follicle, where fluids are produced and sent to the body’s surface via the hair follicle’s funnel (Khan et al., 2022). The major function of sebaceous glands is lipid synthesis, and their products cover the skin, acting as a protective and insulating layer. When the sebaceous glands malfunction, it results in increased lipid output or changes in sebum composition, both of which are associated with the development of acne to some extent. Studies have found that polymer nanocarriers can aggregate not only at hair follicles, but also through excretory ducts at sebaceous glands. As a result, while the sebaceous gland is the primary source of acne, it can also be used as a target for pharmaceutical therapy. However, excessive sebum production may limit drug delivery to some extent. Researchers are particularly interested in how to adjust drugs’ oil/water distribution coefficients or the physicochemical properties of carriers.

Between the infundibulum and isthmus, a variety of cell populations exist, particularly immune cell populations (antigene-presenting cells, macrophages, and lymphocytes) surrounding the upper hair follicle (Chambers & Vukmanovic-Stejic, 2020). Furthermore, investigations have demonstrated that an inflammatory reaction occurs throughout the entire acne growth process (Kanti et al., 2018), implying that hair follicles may be a target of percutaneous vaccination for acne treatment. Acne vaccinations that are currently available include a cell wall-anchored sialase vaccine (Yu et al., 2022), a pathogen-based death vaccine (Nakatsuji et al., 2008), and a monoclonal antibody CAMP factor vaccine (Wang et al., 2018). It is unusual to see topical acne therapy using polymer nano-delivery devices containing these related antibodies.

The bulge is the arrector pili muscle’s attachment site. It is a potential target for regenerative medicine research because it has a high concentration of hair follicle stem cells with high proliferation and differentiation potential, which are involved in maintaining and controlling hair development as well as being in charge of hair follicle reconstruction and regeneration. Below the bulge is the lower part of the hair follicle with cyclic circulation, including superfollicle and hair bulb. Dermal papillae in the hair bulb, like hair follicle stem cells in the extension, can receive and send signals to trigger hair follicle regeneration and pigmentation, which is one of the goals of regenerative medicine research (Abreu & Marques, 2022). Furthermore, the bottom region of the hair follicle can influence follicle penetration via hair cycle activity (physical transport).

In conclusion, hair follicles can not only provide additional therapeutic targets(infundibulum, sebaceous glands, perihair follicle cell population) for the treatment of acne by polymer nano drug delivery system, but also provide corresponding targets(bulge, hair bulb, etc) for other hair follicle-derived diseases such as alopecia areata and hirsute disease.

3. Effect of polymer carrier on hair follicle delivery

The hair follicle’s complex structure suggests that it can be used as a drug delivery target and has the potential for topical drug delivery, but its complex three-dimensional structure and physiological function suggest that drug penetration through the hair follicle may be a complex process influenced by a variety of factors.

The physical and chemical properties of polymer nanocarriers influence their penetration of hair follicles, and their particle size, surface charge effect, carrier composition, surface modification, and so on will play a significant role in determining whether drugs can be effectively targeted into hair follicles to treat acne.

3.1. Particle size

Particle size is the primary factor affecting the polymer nanodrug delivery system into the hair follicle. Patzelt et al. (2011) investigated the penetration sites of PLGA polymer nanoparticles with various particle sizes (122 nm, 230 nm, 300 nm, 470 nm, 643 nm, and 860 nm) into hair follicles. Small particles of 122 nm and large particles of around 860 nm targeted the infundibulumof hair follicle, while the medium particles of 300 to 470 nm could target the sebaceous glands. As a result, Selective targeting of different parts of pig hair follicles can be achieved by changing the particle size. Because pig skin is physiologically and anatomically similar to human skin, the experimental results in pig hair follicles are expected to be replicated in human hair follicles. Rancan et al. (2009) discovered that PLA nanoparticles with particle diameters of 228 nm and 365 nm may enter villi hair follicles and reach sebaceous glands. Główka et al. (2014) observed that when polymer nanoparticles with sizes of about 300 nm were incorporated in organic gels, they gathered preferentially in sebaceous glands. These investigation confirms that medium-sized particles target sebaceous glands preferentially. In contrast to Alexa Patzelt’s conclusion, Sahle, Gerecke, et al. (2017) discovered that nanogel with particles of 500 nm may target deeper into the hair follicle than that with particles of 400 nm, possibly due to the pumping effect of hair. In addition, the 440 nm nanoparticles were found to penetrate the dermis surrounding the hair follicle. Brice Mahe (Vogt et al., 2006; Mahe et al., 2009) discovered that 40 nm or 200 nm polystyrene nanoparticles could transfer vaccine components to antigen-presenting cells via the hair follicle route, suggesting that a polymer nanocarrier system could be used to deliver vaccine components to the skin of acne patients. Alvarez-Román et al. (2004) discovered that polystyrene nanoparticles with particle size of 20 nm were more likely to gather in hair follicles than those with particle size of 200 nm, implying that particle size may influence the aggregation of active components at the target site.

3.2. Surface charge

The surface charge effect is one of the important factors affecting the polymer delivery system into the hair follicle. In order to better understand the effect of surface charge of polymer nanoparticles on skin penetration, Contri et al. (2016) investigated the skin penetration of cationic and anionic acrylic nanocapsules. The results showed that cationic nanocapsules had better permeability than anionic nanocapsules. Furthermore, embedding cationic polymer nanocapsules in chitosan gel can improve its permeability, which is speculated to be related to the properties of the nano-gel itself. By enhancing skin hydration, it promote the flow of lipid bilayer in the hair follicle region, allowing the gel containing cationic polymer nanocapsules to target deeper into the hair follicle. Venuganti & Perumal (2009) modified the surface of G2 PAMAM dendritic polymer and synthesized cationic, neutral, and anionic dendritic polymers with amine, acetyl, and carboxyl terminations to explore the effect of surface charge on carrier penetration. These dendritic polymers were labeled with FITC and its skin penetration was studied by pig skin experiment in vitro. The results showed that the cationic dendrimer had a higher permeability than the other two. Furthermore, iontophoresis improved cationic and neutral dendritic polymer infiltration, demonstrating that external stimuli can aid hair follicle penetration. According to the preceding two research, Cationic polymers, whether polymer nanoparticles or dendritic polymers, exhibit higher permeability. This could be because cationic polymers are easy to adhere to negatively charged cell membranes, thus increasing their permeability, but at the same time, they also lead to the destruction of skin cell membranes and the generation of reactive oxygen species (Contri et al., 2014; Davies et al., 2017). Cationic polymers are thus more toxic than anionic polymers. To enhance the efficiency of cationic polymers in the future, researchers must investigate ways to reduce their toxicity. Ebrahimi et al. (2021) demonstrated that it is feasible to locally treat skin diseases such as acne by cationic nanocapsules loaded with tretinoin(TTN). In order to reduce the toxic effect of cationic polymer on cells, this study embedded TTN-loaded nanocapsules in nanogel, thus alleviating its stimulation on skin cells.

3.3. Materials used in carrier composition

Polymer nanocarrier materials also play an essential role in hair follicle penetration both natural and synthetic polymers can be used as carrier materials targeting hair follicles and sebaceous glands. The researchers discovered that the drug accumulation of nanocarriers(such as Bpo-PF127-PNPs, Ada-TPGs-PNPs, and IST-DLX-NPs) in hair follicles, prepared by different materials that include Poloxam (Pluronic f127) (Ogunjimi et al., 2021), 2D-alpha-tocopherol polyethylene glycol 1000 succinate (TPGS) (Kandekar et al., 2018), and natural galactoman (DLX) (Kahraman et al., 2016), was three times higher than that of commercial BPO, ADA, and IST gels, demonstrating that these materials could impact follicle penetration.

Tolentino et al. (2021) first evaluated the ability of clindamycin-loaded chitosan nanoparticles (CS-NPs) and sodium hyaluronate nanoparticles (HA-NPs) to target drug delivery to hair follicle and sebaceous glands, and make the two vectors comparable by adjusting the preparation method. The two carriers, for example, had similar particle sizes (362 ± 19nm and 417 ± 9nm), pH (about 6 near to skin pH), and encapsulation rates (42% and 48%). Despite having diametrically opposing surface charge properties, their moduli are similar (+27.7 ± 0.9 mV and −30.2 ± 2.7 mV). The findings demonstrated that both nanoparticles could target sebaceous glands compared with commercially available clindamycin gels, and their targeting was better in oily skin. Moreover, the clindamycin encapsulated in HA-NPs increased more significantly in the accumulation of sebaceous gland than that in CS-NPs.

3.4. Surface modification

Although optimizing polymer particle size and surface charge can achieve passive targeting to hair follicle, its low permeability remains a challenge. Therefore, based on the changes in the microenvironment of acne lesions, polymeric nano-delivery carriers used for drug delivery can achieve active targeting to hair follicles by modifying the surface with ligands. During the development of acne, the microenvironment of the hair follicle appear changes, such as elevated pH (Proksch, 2018), higher temperature (Dréno et al., 2018), and oxidative stress imbalance (Md Jaffri, 2023). Therefore, depending on the microenvironment, functional polymer nanocarriers targeting hair follicles can be designed, and the carriers can be combined with external mechanisms such as near-infrared irradiation and magnetic fields to obtain better targeting effect.

In the pathological conditions of acne, excessive production of reactive oxygen species (ROS) in the hair follicle microenvironment leads to an oxidative stress imbalance. Based on this characteristic, Rancan et al. (2021) created rapamycin (mTOR)-loaded chitosan (CMS) nanocarriers and prepared reduction sensitive (rsCMS) or oxidation sensitive (osCMS) nanocapsules by altering the inner shell of mTOR-CMS nanocapsules (introducing dithionyl or thioether groups). The results demonstrated that in a simulated inflammatory skin environment in vitro, osCMS nanocapsules were superior to rsCMS and could selectively deliver mTOR drug to the site of skin inflammation, achieving targeted drug delivery.

According to the pH changes in the hair follicle microenvironment during acne pathogenesis, Sahle, Gerecke, et al. (2017) prepared pH-sensitive nanoparticles (NPs) loaded with dexamethasone (DxPCA) using different materials (cellulose phthalate, acrylic acid) via nano-precipitation method…The nanoparticles prepared from these two materials have a high drug loading capacity and encapsulation efficiency, with particle sizes ranging from 100 to 700 nm. The results revealed that pH-sensitive nanoparticles made of different carriers could dissolve and release in various areas of the hair follicle, and those made of sodium cellulose phthalate performed better than acrylic acid. As a result, the creation of ph-sensitive nanoparticles based on the acne microenvironment has a high potential for targeted transport to various sections of the hair follicle. Furthermore, the experiment demonstrates that the pH response is influenced by the structural composition of nanocarrier.

4. Combining with other technologies

By changing the physicochemical properties of the polymer carrier, it can promote the delivery of drugs to the hair follicle site to exert the advantages of targeted delivery, but due to the limited drug load of the carrier, there are certain limitations for the use of transdermal delivery drugs or biomacromolecular drugs that require large doses. Therefore, combining nanocarriers with physical osmotic technologies such microneedles, iontophoresis, ultrasound, photothermal, magnetic fields, and others can fully exploit numerous benefits and synergies to obtain superior hair follicle delivery effects.

4.1. Iontophoresis technology

Iontophoresis is a minimally invasive physical osmotic approach that uses a low voltage or current density to push charged medication molecules into the skin (Andrade et al., 2023). Iontophoresis enhances drug permeability to the skin while decreasing medication effective accumulation. As a result, some researchers believe that combining polymer nanocarriers with iontophoresis can overcome the problem of drug building in hair follicles, resulting in improved local drug delivery and more efficient treatment of hair follicle illnesses (Takeuchi, Suzuki, et al., 2017). Venkata Vamsi Venuganti tagged cationic, neutral, and anionic dendrimers with FITC to investigate the effect of dendrimers combined with ion-introduction approach on targeting of drug delivery carrier to hair follicles. The results showed that the accumulation of cationic and neutral dendrimers increased in hair follicles. This could be due to better permeability or affinity of cationic and neutral polymers. In contrast to Venkata Vamsi Venuganti’s findings, Tomoda et al. (2011); Takeuchi, Suzuki, et al. (2017) discovered that the combination of negatively charged polylactic acid-glycolic acid (PLGA) nanoparticles loaded with indomethacin with ion-introduction therapy could result in the accumulation and release of negatively charged PLGA nanoparticles in the hair follicle. This showed that different polymer nano-delivery carriers may have varied penetration mechanisms, resulting in diverse accumulation patterns in hair follicles.

4.2. Microneedle technology

Microneedle is a new type of drug delivery preparation between hypodermic injection and transdermal patch, which can puncture the skin stratum corneum and form a short reversible micro-channel to significantly improve the drug delivery efficiency (Yang et al., 2021). Therefore, meticulous screening of medication relative molecular mass, solubility, and other properties is no longer required for transcutaneous drug delivery, allowing large molecule antibodies (Ding et al., 2023), proteins (Yuan et al., 2022), or vaccines (Li et al., 2020) to be delivered, significantly widening the spectrum of therapeutic application. Polymer nanocarriers made of different biomaterials, such as chitosan and polylactic acid-glycolic acid, have been proven in studies to be transported to immune cells around hair follicles by different types of microneedles (soluble microneedles and hollow microneedles) to trigger an immunological response (Zaric et al., 2015; Wan et al., 2021; Mohsin et al., 2022). When compared to microneedles, polymer carrier-based microneedle technology can improve antigen delivery to immune cells and boost cellular immunity (Chen et al., 2018; Zhang et al., 2023). As a result, the combination of the two can not only play the role of microneedle physical permeability, but also of prolonged controlled release and targeted carrier distribution.

4.3. Ultrasound technology

Ultrasound introduction is a technique that employs low-frequency ultrasound energy to break the skin’s stratum corneum, allowing the medicine to be absorbed through the skin. Its osmotic mechanism is diverse, as it can not only change the orderly structure of the stratum corneum by mechanical high-speed vibration, but also achieve accumulation by rotating the flow of surrounding particles and liquid to produce microflow to promote drug flow to hair follicles. Combining ultrasonic introduction with polymer nanocarriers, according to some researchers, can boost medication accumulation in the skin (Bioeffects Committee of the American Institute of Ultrasound in Medicine, 2022). Huang et al. (2015) explored the effect of ultrasound on the penetration of diclofenac (DF)-coated polyamide amine dendritic polymer (PAMAM-G3) into hair follicles. They compared the cumulative dose of DF gel, DF PAMAM-G3 dendritic gel, and DF PAMAM-G3 dendritic gel combined with ultrasound on the skin. The results showed that the drug permeability of DF-PAMAM-G3 dendritic gel was higher than that of DF gel, and the skin permeability of DF-PAMAM-G3 dendritic gel combined with ultrasound was 3.6 times higher than that without ultrasound, confirming that the dendritic polymer combined with ultrasound can improve the permeability of active chemical. Rangsimawong et al. (2015) found that although the combination of ultrasonic technology with nanocarriers could boost drug penetration into hair follicles and enhance drug release, ultrasound might lead to the closure of hair follicles, thus lowering the drug delivery efficiency of the nanocarriers. Therefore, the use of ultrasonic in combination with polymer delivery system to target hair follicles must be carefully considered (Manikkath et al., 2017).

4.4. Magneto-optical

In addition to the common Red light therapy, fractional laser, intense pulsed light (IPL), photothermal therapy are becoming more popular for treating acne (Correia et al., 2021). Photothermal therapy exposes the photothermal agent to a specific wavelength through electromagnetic radiation to induce ion resonance of ions, thereby inhibiting sebaceous gland secretion or directly killing Propionibacterium acnes (Lin et al., 2019; Kly et al., 2023). Among them gold nanoparticles (GNPs) are notable for their biocompatibility, ease of modification, and unique tunable optical and electromagnetic properties. According to study, GNPs can be modified by hydrophilic or cationic polymers to offer high-performance delivery methods. Therefore, when the carrier (Tanner et al., 2011) of the polymer nanodrug delivery system is an inorganic nanocarrier (GNPs), the hair follicle can be reached by exogenous stimuli such as magneto-optical. Mahmoud et al. (2017) believed that the surface functional group of GNP determines whether it can target different parts of the skin, so GNR was prepared in neutral, anionic, cationic, and hydrophobic polymers, and the results showed that hydrophobic polystyrene PS-GNR accumulated the most effectively in hair follicles. This suggests that polymer-modified GNR may be a promising approach to target hair follicles for the treatment of hair follicle-associated disorders.

To summarize, the combination of polymer nano drug delivery carrier and physical enhancement strategy is expected to increase the targeting of drug delivery carrier. Nevertheless, the specific application must be researched and explored further.

Based on the summary description of Part III and Part IV, three strategies of targeting hair follicle drug delivery with polymer carrier were proposed. Frist, by adjusting the composition material and production technique of the polymer nanoparticle delivery carrier to change the particle size, the drug can reach the hair follicles directly to complete the accumulation and perform the anti-acne role. Second, the pH, temperature, and oxidation level of the hair follicle microenvironment will alter as acne develops. Therefore, by modifying the surface of the carrier to prepare different responsive polymer carriers, the carrier can be targeted to gather in the hair follicle. Third, integrating polymer nanocarriers with other technologies can improve vector accumulation at the hair follicle site and even reach the cell population surrounding the hair follicle, providing a way for polymer nanocarrier-based acne percutaneous immunotherapy (Figure 1).

Figure 1. Three strategies for targeting hair follicles with polymer nano drug carrier (By figdraw).

5. Application of polymer carriers in hair follicle targeted treatment of acne

According their structural features, polymer nano-delivery systems can be further divided into polymer nanoparticles, polymer micelles, nanogels and dendrimers depending. Different types of polymer nanodrug delivery systems have their own characteristics, therefore, it is very important to select or construct appropriate polymer nanodrug delivery systems to target hair follicles for acne treatment.

5.1. Polymer nanoparticles (PNPs)

Polymer nanoparticles are colloidal particles made of natural or manmade polymers. The particle size ranges from 10 to 1000nm (Lu et al., 2011). When the particle size of PNPs exceeds 50 nm, they form a rigid structure with little deformation capacity, making penetration into the stratum corneum problematic. In general, they enter the deep skin through the hair follicles and target specific locations. As a result, PNPs are more stable than the other three polymers. According to study, the particle size of PNPs influences drugs penetration and deposition in hair follicles. PNPs with particle sizes ranging from 300 to 1000 nm were found in the infundibulum (Lauterbach & Müller-Goymann, 2015) and less than 300 nm have been found to reach the sebaceous glands and even deeper. Smaller than 40 nm particles can enter the perifollicle cells. Thus, PNPs of smaller size might penetrate deeper into the hair follicle and aggregate in base of hair follicle to achieve long-term sustained drug release. Based on the topical skin penetration mechanism of PNPs and the influence of varying particle sizes on the penetration sites, Reis et al. (2014) used self-emulsifying technology and poloxam as a stabilizer to design polylactic acid - glycolic acid (PLGA) polymer nanoparticles containing Azazic acid (AZA). The results demonstrated that AZA-PLGA-PNPs can target the hair follicles and sebaceous glands by altering the particle size, exerting the effect of acne treatment. Similar to the other three polymers, cationic PNPs enter hair follicles more easily than anionic PNPs, probably due to interactions between carriers and skin cells. Saeed Ebrahimi optimized the formulation of cationic acrylic nanocapsules (LCNC) loaded with tretinoin (TTN) using the Box-Behnken method to achieve the optimal particle size and encapsulation rate. The results showed that TTN-LCNC is a feasible local treatment for acne and other skin diseases. Furthermore, embedding TTN-LCNC in nano-gels (HGs) can lessen the harmful effect of HG-TTN-LCNC cationic polymer on cells and alleviate the irritation on skin cell. Therefore, for PNPs, optimizing the physicochemical features of their carriers (such as particle size, surface charge, etc) can not only improve their penetration in hair follicles, but also target hair follicles and their appendages (sebaceous glands).

Furthermore, based on changes in the microenvironment (pH increase) of the hair follicle produced by acne, PNPs can be surface-modified to create pH-sensitive PNPs. Fitsum Feleke Sahle (Dong et al., 2019) employs electron paramagnetic resonance (EPR) to assess and quantify spin-labeled medicines in a noninvasive manner. Researchers are investigating the skin penetration and drug release capabilities of PH-sensitive polyacrylic resin I (Eudragit^®L-100) nanoparticles containing spin-labeled dexamethasone (Dx). The findings showed that DxPCA-Eudragit ^®L-100NPs can be targeted to hair follicles, delivering DxPCA to the deeper active epidermis and dermis to treat skin conditions like acne.

Furthermore, PNPs can be combined with external factors such as iontophoresis, ultrasound, microneedles to achieve active targeting of hair follicles and hence have an anti-acne role. Some reported PNPs targeting hair follicle for acne treatment are presented in Table 1.

Table 1. Reletive information of some PNPs targeting hair follicle for acne treatment.

Drugs	Carrier composition	Size(nm)	Zate(mV)	Target site	Stimuli	References
Tretinoin	Eudragit RS100	116.3	30			(Ebrahimi et al. 2021)
Clindamycin	Chitosan	362 ± 19	+27.7 ± 0.9	sebaceous glandunits		(Takeuchi, Suzuki, et al. 2017)
	Yaluronic acid	417 ± 9	−30.2 ± 2.7
Azelaic acid	PLGA	252.23 ± 23.1	11.3 ± 1.4	follicularunit		(Reis et al. 2014)
Dexamethasone	Eudragit^®L100	303.1 ± 5.5		HFs orinner root sheath	pH-sensitive	(Dong et al. 2019)
Tretinoin	Poly-ɛ-caprolactone	CCM:228 ± 0.8 SFO:222 ± 0.8	CCM:-7.27 ± 0.66 SFO:-5.72 ± 1.36			(Ourique et al. 2008)
Tretinoin	Polyolprepolymer-2			follicularopening and top of the PSU		(Skov, Quigley, and Bucks 1997)
Adapalene	ABA triblock copolymer PEG5K-b-oligo			HFs and upper epidermis		(Ramezanli, Zhang, and Michniak-Kohn 2017)
Benzoyl peroxide	Chitosan	approximately 50		P.acnes		(Friedman et al. 2013)
Clindamycin HCl	Carboxymethyl chitosan	318.40 ± 7.56			Ultrasound-assisted	(Chaiwarit et al. 2022)
Spironolactone	Poly-ε-caprolactone	180.0 ± 1.6/126.8 ± 1.0	−15.3 ± 1.3/ −12.1 ± 2.4	HFs		(Ferreira-Nunes et al. 2021)
	EL100	102.7 ± 7.1	−19.0 ± 1.2
Adapalene	Eudragit^®EPO	125.8 ± 3.5	18.4 ± 2.9		Acid-Responsive	(Folle et al. 2021)
Thymol	PLGA	below 200	around − 28	HFs and P.acnes		(Guo et al. 2014)

5.2. Polymer micelles (PMs)

Polymer micelles are made up of amphiphilic polymer nanocarriers that form spontaneously in a selected solvent and have a structure of "hydrophobic core - hydrophilic shell" (Zhang et al., 2022). The micelle’s hydrophobic core is utilized to embed insoluble medicines in order to improve drug bioavailability, while the micelle’s hydrophilic shell can stabilize the micelle and affect its pharmacokinetic behavior in vivo.

Compared to the other three polymers, Polymer micelles are the best carriers for increasing the solubility of insoluble pharmaceuticals. Retinoic acid (RA) is a widely used vitamin A derivative that heals acne by lowering sebum production and inflammation. However, its poor solubility may result in poor absorption and various degrees of skin irritation (Milosheska & Roškar 2022). Lapteva et al. (2015) created PMs using biodegradable and biocompatible diblock methoxy-poly(ethylene glycol)-poly(hexylsubstituted lactic acid) copolymer (MPEG-dihexPLA) to increase RA solubility, decrease RA doses, and improve efficacy and safety. To ensure complete release of the RA contained in micelles, acetonitrile diluted at 1:20, 1:50, and 1:100 was added to the micellar system, then centrifuged and passed through the membrane, and the RA content was determined using HPLC. The results showed that the RA solubility of the polymer micellar system was improved by 400 times.

Both PMs and PNPs permeate the skin in the same way. They arrive deep into the skin via hair follicles and target specific locations. Their particles sizes ranges from 20 to 200 nanometers. Using a confocal laser scanning microscope, Maria Lapteva compared the biopsied pig skin tissues containing sebaceous glands (PSU) and those without PSU, and found that the deposition of micelles with the optimal formulation in biopsied tissues containing PSU was twice as high as that without PSU. Based on these findings, Maria Lapteva performed a similar experiment on human skin tissue, turning out that polymer micelles can be targeted into the sebaceous glands of human hair follicles. Then, the micelles generated under optimal conditions were compared with two types of marketed gels (polymer nanospheres gels and ordinary gels) loaded with RA, showing that the polymer micelles could not only be used as RA nanocarriers, but also exhibited selective targeting of PSU (Bachhav et al., 2011; Lapteva et al., 2014), which could reduce drug dose and improve drug safety, and finally play a role in acne treatment. Some reported PMs targeting hair follicle for acne treatment are presented in Table 2.

Table 2. Reletive information of some PMs targeting hair follicle for acne treatment.

Drugs	Solubility	Carrier composition	Size(nm)	Target site	References
Adapalene	Almost insoluble in water	CMC-Na	Below 20	HFs	(Kandekar et al. 2018)
Benzoyl peroxide	Low water solubility	Pluronic^® F127	25.3 ± 0.3	HFs	(Kahraman et al. 2016)
Retinoic acid	Insoluble in water	mPEG-dihexPLA	71.7 ∼ 105.7	PSU	(Lapteva et al. 2015)
Lauric acid	Insoluble in water	PCL-PEG-PCL	Below 100	P. acnes	(Tran et al. 2016)
Isotretinoin and Clindamycin phosphate	Insoluble in water and highly water soluble	Phosphatidylcholine	19.3 ± 1.03	P. acnes	(Sharma et al. 2021)
Spironolactone	Low water solubility	mPEG-dihexPLA	20	PSU	(Dahmana et al. 2021)

5.3. Nano-gel (NGs)

Nanogel is a three-dimensional hydrogel with nanoscale formed by swelling crosslinked polymer network. It possess the characteristics of hydrogels (high moisture content, adjustability, and biocompatibility) as well as nanoparticles (large specific surface area, nanoscale size) (Ramos et al., 2014). In the transdermal absorption pathways, nano-gels differ from the other three polymers. Aside from absorption via the accessory channel of hair follicles, nano-gels can also improve the mobility of the lipid bilayer in the stratum corneum (Giulbudagian et al., 2016) by increasing skin moisture, which may be determined by their inherent characteristics.

Compared with the other three polymers, functional nanogels have advantages in targeting hair follicles for acne treatment. Nanogels have a high inclusion capacity for guest molecules(transfersomes (Vasanth et al., 2020), ethiosomes (Salem et al., 2021), nanocrystals (Tang et al., 2022), niosomes (Budhiraja & Dhingra, 2015), ethosomes (Yu et al., 2016), nanospheres (Sallam & Marín Boscá, 2017), nanocapsules, dendritic polymers, polymer micelles, etc.) due to their biocompatibility. By modifying groups sensitive to internal or external triggers (pH responsive type, thermal responsive type, oxidation reduction type, etc.), functional nanogels or hybrid nanogels (combined with different polymers or nanoparticles such as magnetic nanoparticles, carbon nanoparticles, gold nanoparticles) can be manufactured to achieve regulated drug release or drug delivery to the target region.

Acne may influence the microenvironment of the hair follicle, causing changes in pH, temperature, and oxidative stress. Therefore, The creation of functional polymer nanogels based on the microenvironment of the hair follicle is presently a research hotspot.

Throughout the acne development phase, inflammation is prevalent. When an acne lesion becomes inflamed, the skin temperature rises above that of the surrounding normal skin. Based on this, Rancan et al. (2017) create a thermo responsive polyglycerin nanogel (dPG-tNG) based on dendritic polyglycerin(dPG) and methoxy-polyethylene glycol-propyl ether-coethylene glycol. The findings revealed that, in addition to excellent delivery performance, tNG may improve selective drug delivery to skin lesions by external infrared radiation (IR) stimulation, implying that tNG can sense the skin temperature of acne lesions. Furthermore, it was discovered that perifollicular immune kinds of cells such as dendritic cells could internalize tNG, implying that modified polymer nanocarriers could target perifollicular cells to reduce acne inflammation and produce therapeutic benefits. Pathogenic consequences of acne inflammation include the production of reactive oxygen species, which can lead to oxidative imbalance. Therefore, in view of the changes of hair follicle microenvironment under acne pathologic conditions, the preparation of oxidized polymer nanoparticle delivery carriers for acne treatment is a feasible direction.

Furthermore, acne lesions occur on the skin surface, and exogenous stimuli are more likely to approach the lesions, which provides research prospects for the treatment of acne diseases by photothermal, ultrasound and microneedles. Some reported NGs targeting hair follicle for acne treatment are presented in Table 3.

Table 3. Reletive information of some NGs targeting hair follicle for acne treatment.

Type of NGs	Drugs	Carrier composition	Size(nm)	Target site	Stimuli	References
Dendronized polymer	dexamethasone and betamethasone	poly(N-isopropylacrylamide)	95 ± 1.9	SC	Temperature	(Giulbudagian et al. 2016)
Transfersome	Adapalene	Carbopol 934	354.22	SC	pH	(Vasanth et al. 2020)
Ethosomal	Retinyl Palmitate	Chitosan	195.8 ± 5.45	SC		(Salem et al. 2021)
Nanocrystal	Tanshinone	carboxymethyl chitosan and oxidized hyaluronic acid	223.67 ± 4.03		pH	(Tang et al. 2022)
Niosomes	Rosemarinic acid	Carbopol 940	814.2			(Budhiraja and Dhingra 2015)
Ethosomes	Cryptotanshinone	Carbopol 974 and PEG-400	69.1 ± 1.9			(Yu et al. 2016)
Nanospheres	Adapalene	poly-ε-caprolactone/ HPMC/HA	107.5 ± 8.19	Epidermal layer and HFs		(Sallam and Marín Boscá 2017)
Nanocrystal	Curcumin	CMC-Na	267	the lower part of the infundibulum of a HFs		(Pelikh et al. 2021)
Nanocrystal	Azelaic acid	Pluronic^® F127	269.9 ± 14.8	SC		(Tomić et al. 2021)
Niosomes	Cryptotanshinone	Polyacrylate 700	less than 150	epidermis		(Wang et al. 2020)

5.4. Dendritic polymers (DPs)

Dendritic polymer is an innovative type of drug delivery carrier. It has a precise three-dimensional spatial structure and is made up of a core, repeating dendritic units beyond the core, and surface functional groups. It has been investigated for use in topical drug delivery (Araújo et al., 2018). Each dendritic unit is called to as a generation. The more dendritic units, the higher the algebra, the tighter the binding, the more surface functional groups, and the stronger the activity (Cheng et al., 2008). Lower generation dendritic polymer (G2) has a looser structure, which can interact with the lipid bilayer, making it easier to penetrate the epidermis, whereas higher generation dendritic polymers typically deliver drugs via the hair follicle. Gökçe et al. (2021) used confocal microscopy to examine the skin penetration pathway of a G2 polyamide amine (PAMAM) dendritic polymer loaded with fluorescently labeled ADA, and the results showed that ADA-PAMAM dendrimers can be targeted into hair follicles, implying that dendrimers may be effective topical drug delivery systems with potential hair follicle-targeting effects.

The surface charge is related to DPs penetration effects. Venkata Vamsi Venuganti synthesized cationic and anionic dendritic polymers having amine and carboxyl groups, respectively, and examined their skin penetration via pig skin in vitro. The results showed that compared with anionic dendrimers, the cationic dendrimers modified by amino groups increased drug accumulation in hair follicles.

Dendritic polymers are relatively dangerous in compared to the other three polymers and varied types of dendrimers have different toxicity. For example, high-generation dendrimers are more toxic than low-generation dendrimers, and cationic dendrimers are more toxic than anionic dendrimers (Kim et al., 2018; Diaz-San Segundo et al., 2021). Thus limiting the use of dendritic polymers in targeting hair follicles for acne treatment. The development strategies for Dendritic polymer is modification, including acetylation or pegylation of dendritic polymers, to achieve cation neutralization and cytotoxicity reduction.

Furthermore, it possesses more drug delivery mechanisms than the other three polymers In addition to the vast cavity of the core being used for drug encapsulation, the dendritic unit can bind drugs by hydrogen bonds or surface groups adsorb the drugs by charge interaction or covalent bond. Therefore, it is a feasible method to use dendritic polymer to encapsulate drugs with low solubility or unstable.

6. Summary and outlook

Targeting hair follicles using polymer nano-delivery technology is a promising concept, but due to the complex three-dimensional structure and physiological function of the hair follicle, how to penetrate polymer carrier into follicular appendages and achieve better follicle targeting also poses new challenges for researchers. Therefore, when designing a polymer nano drug delivery system, the influence of the hair follicle, drug and external stimuli on hair follicle penetration should be considered.

Future study can focus on improving the design of nanocarriers, such as changing the surface charge and particle size, and can be combined with iontophoresis, ultrasonic and other techniques to trigger drug release in order to improve its specificity, effectiveness, and safety in targeting hair follicles.

In addition, Acne immunotherapy and phage therapy using polymer nano-systems may become popular in the future. On the one hand, in addition to the hair follicle’s infundibulum and sebaceous gland, the hair follicle provides an additional target for acne treatment - the perifollicle cell population found between the infundibulum and isthmus. Current research has discovered that at the onset of acne, the inflammatory reaction runs throughout, making it possible to target immune cells near hair follicles to ease the inflammatory response and treat acne. Furthermore, microneedle-based percutaneous immunity is quite mature, and the micropores created by it can provide a conduit for polymer drug delivery carriers to target the immune cell population surrounding hair follicles. On the other hand, long-term topical antibiotic use causes Propionibacterium acnes resistance. Studies have found that phage therapy can achieve the purpose of acne treatment by controlling the colonization of Propionibacterium acnes in the hair follicle area, reducing the inflammatory response caused by it, and restoring the balance of skin microbiota. However, the current phage preparations have the limitations of low stability, short retention time, and inability to target delivery, so the construction of polymer nano-preparations containing bacteriophages to overcome the above problems and achieve the goal of targeting hair follicles for acne treatment may become a difficult and hot spot in future research.

Author contributions

Yujing Lei (First Author): Conceptualization, Data Curation, Resources, Analysis, Visualization, Writing-Original Draft; Wanting Jiang and Cheng Peng: Data Curation, Analysis; Donghai Wu, Jing Wu, Yiling Xu: Resources; Hong Yan (Corresponding Author): Conceptualization, Supervision, Funding Acquisition; Xinhua Xia (Corresponding Author): Conceptualization, Supervision, Funding Acquisition, Writing-Review & Editing; All authors read and approved the final manuscript.

Acknowledgement

We thank the current and former members of our laboratories and collaborators for their contributions to the publications cited in this review article.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Data availability statement

Data sharing is not applicable to this article as no new data were created or analyzed in this study.

Additional information

Funding

This work was supported by the Natural Science Foundation of China (No. 81573621), The Science and Technology Innovation Program of Hunan Province (2021RC4064),Key Discipline Project on Chinese Pharmacology of Hunan University of Chinese Medicine (202302).