Signaling pathway

Both sporadic and nevoid BCC rely on the patched (PTCH)/hedgehog intracellular signaling pathway [5]. Throughout fetal development, this pathway affects the differentiation of several tissues. During embryonic development, it still forms a vital part of the regulation of cell division along with fate.

The hedgehog transcription causes the production of an extra-cellular protein that binds to the receptor network on the cell membrane, triggering a series of events that culminates in cell division [4, 5]. Three human homologs to BCC were found, but the sonic hedgehog (SHH) protein is the closest and most functional match [5–8]. Hedgehog receptor complexes in cell membranes rely on a protein called PTCH to bind ligands. Hedgehog signals are sent to target genes in part by smoothened (SMO), another protein found in the receptor complex [9]. When SHH is available, it binds to PTCH, causing the latter to dissociate from SMO and trigger its activation. The SMO signal is carried to the nucleus by orthologous glioma-associated oncogene homolog (GLI) proteins. PTCH suppresses SMO by binding to it when SHH is not present [10]. It is revealed that mutations inside the PTCH gene reduce the protein-binding capacity with SMO, creating an effect similar to that of the presence of SHH. Hedgehog signaling is unhindered because unbound SMO and downstream GLI are always on. Mutations in the SMO gene may also activate this pathway, allowing for unchecked tumor growth signaling [11]. The hedgehog signaling mechanism in cancer therapy is illustrated in Figure 1.

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Figure 1. 

Hedgehog signaling mechanism in skin cancer therapy

The majority of BCC showed alterations inside PTCH or SMO genes, but the mechanism by which these mistakes cause carcinogenesis is poorly understood [12]. Several researchers believe that disruptions in the hedgehog pathway are necessary for BCC development [13]. Sun-exposed areas are more prone to BCC. The changes of ultraviolet (UV)-specific nucleotide in PTCH as well as tumor suppressor gene tumor protein p53 (TP53) were discovered by Ouhtit et al. [14] to contribute to the beginning of early-stage BCC [15]. In certain cases, concerning BCC, mutations inside the tumor suppressor gene TP53 have been linked to UVR. Another TP53 gene mutation associated with BCC risk is rs78378222, a single-nucleotide polymorphic allele [16]. Fragmentary change (frameshift) in the B-cell leukemia 2 (BCL2) associated X protein (BAX) gene was detected in a small percentage of BCC cases. Reduced levels of BCL2 proteins are characteristic of the infiltrative aggressive BCC class.

Immunology and radiation

Researchers have discovered two different mechanisms by which radiation causes cancer [17]. This primary mechanism is the beginning of extended cell proliferation, which boosts the probability of error in the transcription process, which may lead to cellular transformation. The secondary mechanism is via alteration caused by immediate injury to the DNA during duplication, which may lead to the actuation of proto-oncogenes as well as the deactivation of tumor suppressor genes inside the cells [18].

Constant exposure to UVR suppresses the cutaneous immune system, leading to immunologic insensitivity to cutaneous malignancies, and ultimately the development of BCC [19, 20]. Decreased numbers of thymus cell antigen 1 positive (Thy1⁺) cells, dendritic epidermal T cells, and Langerhans cells are indicative of its local effect. Immunosuppressive chemicals [such as prostaglandin (PG), interleukin 1 (IL-1), interleukin 10 (IL-10), and tumor necrosis factor-alpha (TNF-α)] and the systemic proliferation of suppressor T cells are also deemed harmful to BCC’s growth.

Proteolytic enzymes that repair DNA errors

It has been shown that a group of proteins called mismatch repair (MMR) proteins induce cell death at the G2/M-phase checkpoint in a physiologically relevant way [21]. However, mutated cells can survive since the MMR proteins will fail to detect the DNA damage that they have been pre-conditioned to. In non-melanoma skin cancers, MMR protein levels are elevated relative to the typical skin which confirms MMR abnormal regulation [22]. The most prevalent reason for developing BCC is being out in the sun too much, especially when as a child or young adult. The risk of skin cancer varies depending on where the patient lives. Clinical development of BCC often occurs 20–50 years after UV exposure has occurred [23, 24].

Cancer of the basal cell type is more common at higher elevations and lower latitudes. Climate change and sunbathing, both of which have caused increased exposure to UV, may be central to the rising rates of BCC. Tanning beds and other treatments using UVR have also been associated with enhanced threats to normal basal cell activation while condoning increased mutation. Nevertheless, neither shorter UVB radiation (290–320 nm) nor extended UVA radiation (320–400 nm) are responsible for the development of BCC. UVB radiation from the sun is regarded as the leading cause of skin cancers [25].

Mutations may occur if unprotected DNA is exposed to UV light which can break the nucleic acids’ unsaturated chemical bonds. The ozone layer in the atmosphere blocks all UVC radiation. Melanin absorbs UVA rays, which then transmit free radicals to cellular DNA which then affects the gene’s expression. The translocation of cytosine (C)-C to thymine (T)-T, or C to T, is a common kind of mutation caused by UV light. Tumor formation and proliferation may occur from this process of activating oncogenes or deactivating tumor suppressor genes [26]. While it may recover from superficial wounds, the skin cannot repair internal or genetic damage. This harm accumulates throughout a lifetime with each new episode of sun exposure [27]. Evidence suggests that mutations caused by the TP53 gene proved more frequent for BCC. Although exposure to UV is suggested as a reason for the formation of this mutation, this link has been thus far established solely in 9 chromosomes in affected individuals suffering from familial basal cell nevus syndrome (Gorlin syndrome). The tumor suppressor gene repair is impacted by this mutation [28, 29].

In both sporadic and hereditary types of BCC, the hedgehog signalizing passageway is inappropriately stimulated. Gain-of-function mutations occur in the signaling proteins such as SHH, SMO, and GLI cause (PTCH1), while loss-of-function mutations occur in the tumor suppressor protein and PTCH homologous [30]. Life-span-threat of BCC is somewhat higher for those who are constantly immune-compromised, such as those who have had an organ or stem cell transplant or those who are living with HIV/AIDS [31, 32].

Individuals receiving organ transplants should be advised to restrict exposure to the sun and warned that they could have a higher risk of developing skin cancer. There may be a synergistic relationship between immunosuppression and sun exposure during the progression of skin cancer. Between 65% and 75% of immunosuppressed individuals get skin cancer, a percentage which is 10 times higher than that of the overall population. Recipients deployed for organ transplants have an increased likelihood of contracting skin cancer. Among this vulnerable group, the incidence of skin cancer could hit 100 each year [33, 34].

The skin biopsy imaging method for diagnosing melanoma

A skin biopsy is frequently carried out for the confirmation of the diagnosis as well as the identification of BCC’s histologic species [35]. Generally speaking, a shave biopsy is all that is needed. An excisional or punch biopsy generally requires evaluation of the shallowness of a pigmented abrasion if it turns out to be malignant melanoma since it might be challenging to differentiate between melanoma and pigmented BCC in such cases [36, 37]. Although BCC may usually be diagnosed with a superficial sample that includes the dermis, the tumor formation could be overlooked. For instance, an ulcerated BCC might re-epithelialize with the common epidermis while cancer persists at a deeper level [38]. Although the biopsy of a BCC could comprise half to a full lesion, sampling of the clinical margins should be halted for a definitive diagnosis to be made. Even though they are not often used, punch biopsies are a quick and easy approach to retrieving a substantial specimen. If a tumor is large or has many different morphologies, several biopsies may be necessary to get a confirmed diagnosis [39].

Cytology

Histological confirmation is required for the proper and final diagnosis of BCC for example, the eyelid, and this is often obtained by excisional (punch or shave) biopsy. This method of sampling provides details about the BCC’s histological subtype. Cytology, on the other hand, is a quick option that might potentially provide and help confirm a diagnosis during the first visit [40]. Although its sensitivity in detecting BCC of the eyelid remains unclear, the consensus is that the method is accurate. There is doubt on whether its sensitivity is sufficiently high for use in preoperative surgical planning. Cytology traced through excisional biopsy provides 92% susceptibility and 75% prediction accuracy for diagnosing BCC, according to research by Barton et al. [41]. A comparison was made against those from the secondary set of affected individuals undergoing incisional biopsy, etiology assessment, and abscission with subsequent etiology authentication. This detection rate for BCC was 100% in the second group, and their accuracy in making predictions was 96%.

Ultrasonography

Many are skeptical about using ultrasound technology. Despite its widespread use, ultrasound equipment with high-frequency (20 MHz) and ultra-high-frequency (40–100 MHz) ranges provides only 20% success rate in identifying malignant tumors as opposed to benign ones. Intriguingly, assertions of correct tumor size and depth of invasion are still highly debated [42].

Infrared spectroscopy using a laser Doppler

Ophthalmologists may benefit from using laser Doppler as a complementary technique for distinguishing benign from malignant adnexal skin lesions and identifying the tumor border. The cutaneous perfusion rate in the eyelids is much elevated than in different areas of the human body (e.g., forearm). It has also been established that pretarsal skin has a mean perfusion that is 50% higher than that of perceptual skin. The cutaneous perfusion of patients with eyelid BCC was much greater than that of those without the disease [43].

Artificial intelligence-based system for diagnosis

It has been suggested that artificial intelligence (AI) might be used to aid in the diagnosis of skin cancer at an early stage. Skin cancer detection may be difficult, time-consuming, and costly. AI is being utilized to aid in the detection and treatment of skin cancer [44]. Convolutional neural network (CNN) and deep CNN (DCNN) are two examples of AI-based technologies that have been created to identify and categorize skin cancer [44, 45]. Several mobile health applications have already used AI-based algorithms, making this method readily available to the public [46]. One may save both money and time by using AI for skin cancer screening.

AI-based algorithms for skin cancer identification have been the subject of several research looking at their diagnosis accuracy. One research has shown that both AI-approaches (CNN and DCNN) could accurately categorize photos of different skin lesions in terms of their potential danger [47]. Screenings that may be performed during normal primary care visits or even by the patients themselves were the focus of another research that created a suspicious pigmented lesion (SPL) analysis system utilizing DCNNs to detect skin lesions that warrant further examination [48]. However, how and for whom AI-based algorithms should be used in clinical treatment is still debatable.

Although AI is as good as human dermatologists at spotting skin cancer in dermoscopy images, it may miss the diagnosis if the photo is only taken from one angle or if the lighting is poor. Therefore, doctors should not rely only on AI-based algorithms for skin cancer screening; instead, they should utilize them as one tool among several [49].

Topical treatment

Therapy through radiation

Radiation therapy may be applicable for large wounds along with patients who are not surgical candidates, since BCCs are commonly radiosensitive (e.g., due to allergy from anesthetics, recent anticoagulant treatment, the inclination for the formation of keloids) [74–76]. Recurrence rates for BCC at 2 and 5 years were 2.0% and 4.2% respectively, through the retroactive study of 1,715 histologically compulsive primary cutaneous carcinomas [712 BCCs, 994 squamous cell carcinomas (SCCs), and 9 tumors with definite BCC and SCC properties]. The recurrence rates of SCC were 1.8% in 2 years and 5.8% in 5 years [77]. Patients with aggressive malignancies who underwent surgery may benefit from adjuvant radiation therapy after the procedure [78]. Patients with advanced local BCC undergo absolute remission in about 70% of cases after treatment [79].

Because of its high success rate, radiation was formerly the treatment of choice. However, in view of the effort and expenses involved, it is now used occasionally. Radiotherapy is a realistic alternative for the treatment of recurrent cancers, due to advances in the development of surgical techniques and other therapeutic methods. This option may be saved for more severe or difficult first lesions that need oculoplastic surgery. Moreover, it slows down the need for skin grafting where surgical intervention might leave a big scar.

To treat BCC, PDT has been employed for over 20 years [75, 76]. To photoexcite applied porphyrins on neoplastic and preneoplastic cells, PDT makes use of certain wavelengths of light. The oxygen in the surrounding tissue rapidly soaks up the extra energy, forming singlet oxygen radicals. These free radicals have a rapid cytotoxic effect on the surrounding tissue. In the United States FDA provides only licensed 5-aminolevulinic acid for PDT of actinic keratoses. After sitting for 1 h, the material is exposed to blue light for one minute.

Whether administered orally, intravenously, or topically, PDT localizes into tumor cells before being activated by light exposure (e.g., laser). These treatments are usually only used as a last resort because of their limited efficacy. The cosmetic outcome of PDT is good, but it might cause some unpleasant side effects such as local edema, erythema, blistering, and ulceration [80, 81].

The success rate of PDT in curing superficial BCC was only 50% in research carried out by Calzavara-Pinton et al. [82], whereas it was 83% in curing nodular BCC. For eyelid BCC, PDT had not shown more effectiveness than other standard therapies. PDT with methylaminolevulinate has demonstrated great effectiveness and may be a treatment option for those with BCC in the eyelid, according to research by Puccioni et al. [83].

Drugs that interfere with the hedgehog pathway

Vismodegib

The FDA had approved vismodegib (ERIVEDGE®) as the first-line treatment for the therapy of advanced BCC. SMO, a crucial transmembrane protein in hedgehog signal transduction in malignant epithelial cells, had undergone downregulation [84]. The FDA granted acceptance based on data from a unique, global, and open-labeled research (n = 104). A total of 96 of the 104 people were usable for analysis. Out of 33 individuals, none of them had a complete response. Twenty-two percent (n = 63) of patients suffering from local advanced BCC had limited response whereas 20% showed a complete response [85]. The mechanism of action of vismodegib is described in Figure 2.

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Figure 2. 

The mechanism of action of vismodegib

Sonidegib

In 2015, the FDA approved sonidegib (ODOMZO®), a second HHI. In infective individuals suffering from local advanced BCC refractory to restorative radiation or surgery, or with metastatic BCC, the approval was focused on the BCC outcomes with LDE225 treatment (BOLT) trial. Participants were randomly assigned to receive either 200 mg or 800 mg of sonidegib orally once a day, allocations made according to disease stage, histological subtype, and geographic region. Three affected individuals in the 200 mg group got a complete reaction, while other 35 got a limited response, with a total response rate of 58%. A fraction of affected individuals experienced tumor reduction for at least 6 months, and this number ranged from 1.9 months to 18.6 months [86]. The mechanism of action of sonidegib is described in Figure 3.

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Figure 3. 

The mechanism of action of sonidegib. MYC: myc proto-oncogene protein; CCDN1: cell cycle regulator G1/S-specific cyclin-D1; Sufu: suppressor of fused

Prohibition of checkpoints

Once the hedgehog pathway was suppressed, the first immunotherapy approved by the FDA for advanced BCC was cemiplimab, an inhibitor of programmed death. The drug received full approval in 2021 for treating individuals suffering from local advanced BCC along with fast-track authorization for individuals suffering from metastatic BCC [87].

Study 1620, a phase II, nonrandomized, and open-label investigation, provided the evidence needed to provide clearance for locally advanced BCC. Cemiplimab was administered to patients (n = 112) with locally advanced or metastatic BCC, whose BCC had advanced while on HHI therapy or those who were not eligible for HHI therapy, had severe toxicity, or who were at the end of the intended course of treatment. Both persons with locally advanced BCC [objective response rate of 29% (95% confidence interval: 19–40%)] and those with metastatic BCC [objective response rate of 21% (95% confidence interval: 8–41%)] had high rates of response. Seventy-nine percent of advanced local BCC responders and all metastatic BCC responders had a noticeable duration of response (DOR) for 6 months. The median DOR was not achieved in any treatment group [85].

Micelles for skin cancer

Polymeric micelles have become increasingly important as a drug carrier in recent years for nanoscale drug delivery systems. The majority of skin diseases would benefit from topical drug applications. The properties of the skin barrier have a major influence on the concentration of effective drugs. Although polymeric micelles, a novel drug carrier, are better at delivering drugs through the skin than conventional dosage forms such as cream, ointment, and gel, topical treatment with these products is ineffective due to low drug permeation into the targeted skin layers. Polymeric micelles have many advantages as nanocarriers, including improved drug solubilization in the skin, increased hydrophobic drug separation in the stratum corneum, drug delivery to hair follicles and keratinocytes inside epidermis sheets as well as provision of sustained and slow drug release [88]. It appears that the micelles describe an efficient carrier for targeted drug delivery though the barrier of the skin is altered for dermatological conditions such as acne, psoriasis, and burns [89]. The different applications given by polymeric micelles for the management of skin cancer [90] have been established in Table 1.

Hydrogels for skin cancer

Hydrogels are hydrophilic polymers having a three-dimensional (3D) lattice that can store large amounts of water. Different types of natural or biocompatible synthetic polymers may be utilized for their development [90–93, 95–98]. Due to their distinctive qualities, such as ease of handling, higher water content, tunable mechanical strength, and manageable curing and swelling kinetics. Drug delivery systems frequently use hydrogels, tissue engineering, and wound healing over the past few eras [99–104]. In comparison to other conventional drug delivery therapies, the use of hydrogel-based formulations as an anti-proliferative delivery strategy in melanoma skin tumors offers many benefits [103]. The side effects of this hydrogel formulation were less severe than those of synthetic chemotherapy. By lengthening the half-life of the drug, enabling controlled drug release, and subsequently reducing non-targeted exposure, chemotherapy and gene therapy have both been demonstrated to be more successful when delivered using hydrogel-based drug delivery systems. Researchers have many options with hydrogels to improve cancer drug delivery systems [105]. Various polymers/hydrogel systems employed in the treatment of skin cancer are detailed in Table 2.

Magnetic nanoparticles for skin cancer

Due to a magnetic field’s capacity to functionalize and steer them, magnetic nanoparticles (MNPs) are characterized as cutting-edge tools in the medicinal field. Magnetic elements like nickel, cobalt, and iron, and their oxides are frequently found in MNPs [112]. Hyperthermia, tissue repair, magnetic drug targeting, cell and tissue targeting, improved resolution magnetic resonance imaging (MRI), and transfection are examples of potential MNP biomedical applications. Hyperthermia, which is regarded as a non-invasive cancer treatment methodology, is one of the most promising uses of MNPs and is made possible by the usage of magnetic field-induced excitation of MNPs. Additionally, it has been determined that magnetic iron nanoparticles are an auspicious tool for site-specific drug delivery, and therapeutic and diagnostic tools [113].

Late in the 1970s, the idea of adopting MNPs for targeting tumor cells inside a person’s body to treat cancer first emerged. MNPs can be utilized to heat the tumor and kill it since tumor cells are more susceptible to temperature rise than normal cells. The cancer cells will be damaged by the introduction of MNPs inside tumors, which tend to release energy in the form of heat under exposure to a developing magnetic field [114]. The effective part of MNPs in skin cancer treatment is described in Figure 4.

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Figure 4. 

Role of MNPs in the therapy of skin cancer

Phototherapy in skin cancer

Phototherapy continued as a reliable and frequently chosen treatment option for many dermatoses contempt the development of various efficient systemic medicinal and biological agents for dermatology. The major aspects which subsidize the conquest of disease activity are immune suppression, cell cycle arrest, and altered expressions of cytokines [115]. Psoriasis and other skin conditions can be treated safely and effectively with phototherapy [116]. Dr. Niels Finsen, the 1903 Nobel Laureate for the field of Medicine of Physiology, performed the first UV therapy and showed UV’s beneficial impact on lupus vulgaris, a type of tuberculosis of the skin [117]. Currently, extracorporeal photochemotherapy (photopheresis), narrowband UVB (311–313 nm), broadband UVB (290–320 nm), UVA 1 (340–400 nm), 308 nm excimer laser, and UVA plus a psoralen (PUVA) are used in phototherapy [115]. Essential elements of PDT include photosensitizers. Reduced dark cytotoxicity, tumor-specific aggregation, enhanced photocytotoxicity, reduced skin photosensitivity, and ease of application are all characteristics of an ideal photosensitizer [118]. The detailed applications of phototherapies for skin cancer therapy along with their mechanism are described in Table 3.

Nanoparticles for skin cancer

There is effective as well as appealing methods for treating skin cancer using nanoparticle-based medication delivery. This method boosts therapeutic effectiveness and efficiency by delivering biomolecules to specific locations with little or no side effects [125, 126]. Topical treatments based on nanoparticles are yet to receive commercial approval. For use in dermatology, several technologies using nanoparticles have been developed, manufactured, and controlled [127]. Metallic nanoparticles, which are composed of gold, silver, and metallic oxides, are commercially available and are being researched for use in the dermal delivery of active pharmaceutical ingredients. The particles in the metallic nanoparticles are aggregated on the surface and do not have any adverse effects on the epidermis [128]. These nanoparticle-based formulations have not yet received FDA approval in topical/dermal skin cancer therapy, even though nanoparticle-based therapy is receiving significant awareness and interest for the therapy of skin cancer and different disorders [129]. Clinical trials for NB-001, a brand-new nano-based topical antiviral emulsion, are being conducted for cold sores and herpes labialis which was developed by NanoBio® Corporation [130]. Furthermore, paclitaxel formulations based on nanoparticles are currently being tested in clinical trials to determine their safety, acceptability, and effectiveness in the treatment of cutaneous melanomas under non-melanoma skin cancer [130].

Vinca alkaloids, taxanes, dacarbazine, temozolomide, cisplatin, and nitrosoureas are some of the medications used in skin cancer chemotherapy. Cisplatin is widely used to treat melanoma skin cancer [131]. Actinic keratosis and BCC are two skin cancer disorders that are intensively and widely treated with a different medication called 5-FU. 5-FU has a strong hydrophilic character and may penetrate the subcutaneous layer to reach tumor tissues and approach the target [132].

Dacarbazine is an active medication with a short half-life and low solubility that was used to treat skin cancer. The FDA provides approval for dacarbazine to be used as a single agent for skin cancer therapy due to its anticancer properties. Dacarbazine was a great choice for melanoma skin cancer chemotherapy. To be delivered topically in melanoma skin cancer therapy, dacarbazine is enclosed inside lipid nanoparticles. The FDA also recommended carboplatin as therapy for melanoma skin cancer. It belongs to the class of second-generation drugs with platinum compounds. Through intratumoral injection, carboplatin undergoes loading through polycaprolactone nanoparticles using chitosan-glycerophosphate gel [133]. In 2017, Su et al. [134] created the paclitaxel-loaded copolymer nanoparticles as well as discovered the anticancer impact of carboplatin during in vitro and in vivo testing. Additionally, drugs used to treat melanoma skin cancer are cisplatin, nitrosoureas, vinca alkaloids, taxanes, and temozolomide [135]. Temozolomide was created as solid lipid nanoparticles, and these were used in the administration of temozolomide. For targeting human melanoma cells via an in vitro setting, temozolomide was also delivered via polyamide amine (PAMAM) dendrimer [136]. Ferrous oxide nanoparticles are regarded to be superparamagnetic materials because they acquire a significant amount of magnetic incentive through an exterior magnetic field, making them promising for biomedical applications [137]. They can be used as an MRI contrast because they provide a lot of contrast per unit, requiring just a small number of particles for imaging and lowering toxicity [138]. These particles can transform the energy of an external magnetic field into heat that can be used to treat cancers since tumor cells are more susceptible to high temperatures than healthy human cells [139]. Their utility can be further increased by adding different functional groups to their surface, which improves their biocompatibility and biodegradability. Additionally, polymers that can be added to the surface, such as dextran, cellulose, polylactide-co-glycolide (PLGA), or PEG improve their biodegradability and biocompatibility [140].

The main system that cancer affects is the immune system. Antigen presenting cells (APCs), which include dendritic cells (DCs), make tumor-associated antigens (TAAs) available to T cells in an unstoppable antitumor response. When the receptors were triggered by peptides and major histocompatibility complex (MHC) molecules, the T cells became active. After that, these effector cells pass through the tumor and eventually penetrate the tumor tissue [141]. The entire process will result in the production of the cells necessary for the growth of skin cancer. To overcome these challenges, cytokines were used as the initial immune therapy indication in melanoma skin cancer treatment, which improved patient survival in the long run. This strategy was effective in getting support for its goals of fostering cell proliferation and immune system activation. A high dose was required for the application procedure because cytokines have a limited half-life. Patients experience numerous unneeded side effects as a result of the high amount being administered [142].

The goal of cancer vaccines is to provide potential means, by enhancing the immunological memory of TAAs, to produce enduring reactions to the formation of cancer. DNA- or RNA-based nucleic acid cancer vaccines are also possible. This strategy requires that the DNA or RNA be taken up by the APCs and translated to result in the synthesis of the antigen. Clinical trials revealed no meaningful clinical outcomes despite the intriguing results of the nucleic acid vaccine in melanoma animal models, often due to obstacles to nuclear delivery and immunogenicity. Another innovative method of cancer prevention is TAA peptide vaccination [143].

The concept of gene therapy was developed in 1966, and to put it together, nucleic acids were utilized to replace a damaged or missing gene. Plasmid DNA (pDNA), RNA interference (RNAi), and antisense oligonucleotides (AONs) are three different groups of genetic materials that can be used in gene therapy to cure cancer. Depending on the targeted material from the aforementioned categories, these methods will allow the blow-in or give away of a specific gene. Additionally, manufactured nanoparticles have improved the local application of genetic material transport and transfection. RNAi molecules were also used intratumorally in a variety of ways with liposomes to further the development of effective therapies for melanoma skin cancer management [144].

In a recent study, charged nanoparticles coupled with vaccines eliminated tumors or prolonged life in malignant mice [145]. The researchers said the nanoparticle may be mass-produced, maintained at room temperature, and delivered by general practitioners to treat various tumors. Mice with melanoma tumors were injected with lab-made charged nanoparticles. The nanoparticles helped the adenovirus vaccine-triggered melanoma-fighting cells find the tumor and defeat its defenses (as shown in Figure 5). Five of nine mice given the nanoparticle-adenovirus vaccination combination were cancer-free, while the other four lasted more than 100 days—3 times longer than those given simply the vaccine and 5 times longer than those given nothing. Cytotoxic T lymphocyte cells, which fight cancer, are activated by the adenovirus vaccines. Tumors release chemical signals to appear harmless and avoid discovery.

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Figure 5. 

The image depicts a melanoma tumor complete with its supply of blood and lymph fluid. This zoomed view demonstrates how the charged nanoparticles recruit the body’s immune system to track down and destroy the tumor

Nanogels for skin cancer

Drug delivery devices called nanogels can be used to treat a variety of illnesses. Numerous studies have been conducted on the development of nanogels for medication delivery, especially in cancer theranostics [146]. Ethosomal nanogels may provide promise for skin cancer therapy. This controlled formulation displayed Z-average values of 125.67 nm, apparent zeta potential values of –17.1 mV, and average flux values of 54.72 and 59.83 µg/cm² per hour for drug-loaded ethosome, respectively. The ethosome that was loaded with rhodamine B also reached a depth of 183.82 µm. The analysis of nanogels texture revealed an index in the range of 225.45 g/s for viscosity, 209.34 g for firmness, 189.48 g for cohesion, and 59.45 g/s for consistency. This improved ethosome nanogels significantly reduced the growth of the B16F10 murine tumor cell line (P < 0.05) [147]. Sahu et al. [148] investigated the toxicity and penetration potential of a biocompatible chitosan nanogel encapsulating capecitabine employing an ionic interaction mechanism with pH-triggered transdermal targeting. Using Pluronic F127 as an ion gelation catalyst and Transcutol® as a surface decorating agent to improve non-ionic penetration, the chitosan-capecitabine nanogel (CPNL) was created. The CPNL exhibits fine form and nano size range when studied by transmission electron microscopy (TEM), scanning electron microscopy (SEM), and dynamic light scattering (DLS) analysis with cationic charge and slightly acidic pH assessed by zeta potential and pH analysis. It displayed drug-release properties that were pH-dependent and mimicked the microenvironment of skin cancer. On the human keratinocyte cell line (HaCaT), the CPNL’s apoptotic index and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay exhibited the best cell retention and toxicity after 24 h of treatment. The ex vivo examination of skin penetration revealed notable diffusion and penetration capabilities.

The in vitro anticancer potential of PLGA nanogels loaded with 5-FU (FPNGs) and glazed with nerolidol sesquiterpene was investigated by Rathore et al. [149] in 2021. Both normal PLGA nanogels and FPNGs were created using the emulsification-solvent evaporation process. Nerolidol (2%) sesquiterpene was used as a surface coating to increase the effectiveness of nanogels’ permeation inside the stratum corneum. This size range of the nanogel formulation FPNGs is 220 ± 0.25% nm, as determined through the DLS method. At various pH ranges, the entrapment efficiency was calculated to be around 42% for the release network in a sustained manner over 24 h. Using the HaCaT cell line, confocal microscopy examination revealed the profile of cell uptake and localization. The MTT experiment showed that nanogels were compatible with cells, and the apoptosis assay, which showed an apoptotic index of 0.87, confirmed this experiment. They found that FPNGs are a powerful nanogel system for treating skin cancer that may be used to boost the chemo-therapeutic potency of bioactives with sustained and controlled release at the targeted site [149].

Biocompatible and biodegradable chitin was mixed with the anticancer drug curcumin to form curcumin-loaded chitin nanogels (CCNGs). Curcumin and chitin are both insoluble in water. The produced CCNGs do, however, disperse quite well and steadily in water. DLS, SEM, and Fourier transform infrared (FTIR) analyses of the CCNGs revealed particles in the spherical size range of 70–80 nm. When compared to neutral pH, the CCNGs released more at an acidic pH. Human dermal fibroblast cells (HDF) and A375 (human melanoma) cell lines were used to test the cytotoxicity of the nanogels. According to the findings, CCNGs are less harmful to HDF than melanoma at concentrations between 0.1 mg/mL and 1.0 mg/mL. The apoptotic effect of CCNGs was investigated using a flow-cytometric assay, and the findings indicate that at higher concentrations of the cytotoxic range, CCNGs showed comparable apoptosis to the control curcumin, however, the control chitin nanogels had little impact on apoptosis. In comparison to the steady-state transdermal flow of the control curcumin solution, the CCNGs demonstrated a 4-fold growth. The epidermal horny layer appeared to be loosening in the histological analyses in specimens of porcine skin treated with the produced components, allowing permeation without any visible evidence of irritation. These findings imply that by successfully penetrating the skin, the synthesized CCNGs have unique benefits for melanoma therapy which is the main prevalent and dangerous category of skin cancer [150].

According to Soni et al. [151], cross-linked swell-able polymer networks produce nanogels, which are 3D hydrogel materials with a high capacity to hold water. They do not dissolve into the aqueous media. Nanogels’ size range is from 20 nm to 200 nm and combines the properties of nanoparticles and hydrogels [146, 147]. Nanogels’ gel property makes them able to expand when in contact with bodily fluids [152, 153]. Because of this, they are adaptable in near passage to the target location and increase the circulation of treatments along with drugs. Additionally, the design of nano gels helps in drug release in particular anatomical circumstances [154]. They can easily pass through biological barriers and membranes since they are nanoparticles. They help get medications over the blood-brain barrier. They can avoid the reticuloendothelial system as well. Because of this, nanogels exhibit great stability, biodegradability, and biocompatibility [155]. For the prospective treatment of various illnesses, including but not limited to cardiovascular ailments, tumors, and other malignancies, nanogels are adaptable and suited to be produced in diverse dosage forms. These are just a few of the many distinctive characteristics that nanogels possess [156]. Nanogels can be used in theranostics and medical imaging, and they are effective in medication cocktail therapy. This functionality is crucial for lowering tablet loads and enhancing the effectiveness of various illness conditions’ treatments. In 2018, Tran et al. [157] developed nano-gel formulations containing paclitaxel and 5-FU for combination cancer therapy using PEG methyl ether (mPEG) and chitosan. Using therapeutic agents in combination has greatly improved the efficacy of cancer treatment, however, improving the efficiency of medicine delivery still has problems. According to a study by Liu et al. [158] published in 2022, doxorubicin and olaparib were co-loaded on disulfide bond cross-linked polypeptide nanogels for the treatment of breast cancer in mice models. This drug undergoes immediate release for targeting cancer through nanogel when a high glutathione environment is stimulated in cancer cells. In addition, when compared to free drugs and single-drug-loaded nanogels, dual-drug co-loaded nanogels exhibit the highest anticancer activity and have good biological safety. Doxorubicin and olaparib can therefore be delivered simultaneously using polypeptide nanogels, which has promising potential for usage as a cancer treatment. The most dangerous kind of skin cancer is melanoma. Chemotherapeutic drugs cannot be used topically due to the skin’s physiological makeup, low selectivity, and poor efficacy [148].

Liposomes for skin cancer

Liposomes are effective delivery systems for medicinal medicines because of their hydrophobic lipid composition. Nevertheless, creating the ideal liposome complexity is greatly increased when medicinal medications are delivered effectively to treat melanoma. Targeting multiple pathways to have a cooperative and possibly synergistic effect, lengthening circulation time in the body using PEGylation or other modifications, using a targeted delivery method by conjugating the therapeutic agent to an antibody or peptide, and preventing immune response or toxicity while still protecting the drug or nucleic acids that are encapsulated are all significant considerations. By concurrently targeting many cancer cells, liposomes may represent the next therapeutic advance for melanoma [159]. Compared to more conventional therapy methods like parenteral and oral administration, skin therapies using liposomes are less hazardous. Furthermore, the addition of edge activators to the liposomes results in a less rigid and more flexible bilayer structure, enhancing skin permeability [160]. A team of researchers investigated a brand-new treatment option for SCC. For a cell line in skin cancer that was epidermal growth factor receptor (EGFR)-positive, cetuximab immuno-liposomes significantly increased cellular uptake. Additionally, in comparison with 5-FU solution injection, iontophoresis of liposomes and immune liposomes decreased 5-FU penetration through the skin, which may have a lessening influence on systemic effects. Additionally, when immune liposomes were applied by iontophoresis in comparison to liposomes, significant difference in results were reported [161].

In a study, the effectiveness of co-delivering curcumin and anti-signal transducer and activator of transcription-3 (STAT3) small interfering RNA (siRNA) using cationic liposomes to treat skin cancer was investigated [162]. The curcumin was encapsulated in 1,2-Dioleoyl-3-trimethylammonium propane (DOTAP)-based cationic liposomes and then coupled with STAT3 siRNA. This nano complex’s zeta potential, encapsulation efficiency, and typical particle size were all measured. Cell viability studies in B16F10 murine melanoma cells showed that the co-delivery of curcumin and STAT3 siRNA dramatically reduced the proliferation of cancer cells compared to either liposomal curcumin or STAT3 siRNA alone. The curcumin-loaded liposomes were able to penetrate the skin up to a depth of 160 μm following iontophoretic (0.47 mA/cm²) application. The in vivo effectiveness studies made use of the mouse model for melanoma skin cancer. In comparison to either liposomal curcumin or STAT3 siRNA alone, co-administration of the curcumin and STAT3 siRNA using liposomes significantly slowed the progression of the tumor as indicated by tumor volume and tumor weight. Additionally, the iontophoretic injection of the curcumin-loaded liposome-siRNA combination demonstrated comparable efficiency in preventing tumor growth and suppressing STAT3 protein [162]. PDT is a unique therapy that has the benefits of being able to target tumor cells while sparing normal cells from destruction and not being limited by the size or location of skin lesions. PDT has proven to have several benefits, including low morbidity, minimal functional impairment, greater cosmetic outcomes, and the ability to use it repeatedly several times in one procedure [163]. In practical practice, PDT is an effective treatment for skin malignancies other than melanoma. PDT is being used by more and more clinicians to treat skin cancer patients, particularly older patients. Since 5-aminoulevulinic acid (5-ALA) penetration through the skin is so ineffective on its own, it is crucial to increase delivery efficacy for 5-ALA-mediated PDT, which has been used to treat cancer. According to reports, 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) liposomes are effective 5-ALA delivery vehicles and could one day help in 5-ALA-mediated PDT [164].

According to reports [164], the best topical formulation for BCC patients is one that actively targets tumor cells and delivers an antitumoral drug to the tumor site in a prolonged and regulated manner. All evaluated topical preparations had high bloodstream compatibility. The drug’s permeability tests through the synthetic membrane Strat-M® showed that when liposomes were introduced into the G2 (consisting of Pluronic F-108 and water) gel as opposed to being free, the drug’s permeability was increased. The novel complex systems that were created pass the apoptosis tests with flying colors, their levels of tolerance being in the following order: L4 (5-FU liposome-loaded transdermal formulations) > C1 (oil-in-water emulsion) = G2 > G1 [full-interpenetrating alginic acid sodium salt (AG)-hyaluronic acid (HA) network]. The inclusion of AS1411 aptamer-functionalized liposomes with the C1 cream and G1 gel displays a cytotoxic impact that is more comparable to that of free 5-FU, hence it is advised that they be used as efficient drug delivery vehicles. Antitumor therapy’s therapeutic effectiveness is boosted as a result. Finally, it can be agreed that the G1 gel, which is based on biocompatible AG and HA has demonstrated positive biosafety effects, is the optimal topical formulation from all angles, and may be used as a new therapeutic technique for the treatment of BCC. Skin cancer can effectively be treated by cationic liposome-mediated iontophoretic co-delivery of curcumin and anti-STAT3 siRNA. DOTAP-based cationic liposomes were used to encapsulate the curcumin, which was subsequently combined with STAT3 siRNA. This nanocomplex was unique due to its zeta potential, encapsulation efficiency, and average particle size. Cell viability studies in B16F10 murine melanoma cells showed that co-delivery of curcumin and STAT3 siRNA dramatically reduced the proliferation of cancer cells compared to either liposomal curcumin or STAT3 siRNA alone. In order to effectively treat skin diseases, siRNA and small molecules can be delivered topically using cationic liposomes. Liposomal doxorubicin (Doxil®) has a specific pharmacokinetic profile and tissue distribution, which is reflected in the profile of its toxic effects on the skin. These skin reactions are very different from the ones linked to doxorubicin when it is not liposome-encapsulated. The numerous skin responses linked to the administration of Doxil® are highlighted and shown. Clinicians should be familiar with this range of mucocutaneous adverse effects as this medication becomes more generally known and given.