1. INTRODUCTION

Cyanobacteria are able to produce secondary metabolites with significant bioactivity, including ultraviolet (UV) protective, cytotoxic, antitumor, anti-bacterial, anti-viral, antifungal, anti-in?ammatory, antimalarial, antiprotozoal, and antituberculosis. Cyanobacteria existed billions of years ago on Earth when there was no oxygen in the atmosphere. They were exposed continuously to UV radiation to combat its effects; cyanobacteria developed various mechanisms like the production of UV protecting compounds, antioxidants, and proteins. Cyanobacterial metabolites have various applications in pharmaceutical and biotechnology companies. Natural extracts of plants, pigments, proteins, and flavonoids are widely used for the synthesis of nanoparticles [1,2].

Mankind is becoming more aware that prolonged exposure to UV rays causes a variety of skin problems such as sunburn, wrinkles, skin ageing, hyperpigmentation, and can even lead to skin cancer. The good news is that one can reduce the effects of UV radiation by taking simple protective measures. Blue green algae, or cyanobacteria, contain some of the hottest beauty ingredients, so it’s set a ruffle of beauty feathers. According to the intelligence agency Mintel, blue green showed the biggest skin care trends in 2019 [3]. Cyanobacteria have the ability to retain water and produce UV protective compounds, allowing them to be used as natural UV filters and moisturisers [4]. They are also a rich source of antioxidants that can neutralise free radicals [5]. Nanotechnology offers wondrous, remarkable, innovative solutions for product delivery. New lipid carrier vehicles such as solid lipid, liquid lipid, non-ionic surfactant niosomes, nanoemulsions, and microemulsions possess highly penetrating power, high stabilization and entrapment efficiency, site-targeted drug delivery, and controlled and sustained drug release [5]. Cyanobacterial derived nanoparticles have shown better results due to less time consumption, slow kinetics, low cost, and eco-friendly [6]. Liposomes are suitable for the delivery of various cosmetic creams such as anti-ageing, moisturising cream, beauty, and sunscreen [7]. Lipid carrier and nanoemulsion systems are nanovehicles for moisturising agents. They have the property of retaining moisture, renewing collagen, rejuvenating, and lifting the skin [8]. Nanostructured lipid carriers (NLC) are considered to be the improved version of solid lipid nanoparticles (SLN). NLC offers increased skin hydration and penetration, sustained drug stability, and helps to improve the UV protection system with lesser side effects [5]. This review presents a detailed study on cyanobacterial nanoformulations, improved drug delivery, toxicity assessment rules and regulations, and further determines the beneficial role of these formulations in the cosmeceutical and pharmaceutical industries, as shown in Figure 1.

2. ROLE OF NANOFORMULATION IN DRUG DELIVERY FOR SKIN

Various new formulations have been synthesized for improved drug delivery systems such as nanogels, colloidal systems, nanoparticles, and nanogels [9]. For several skin care problems, numerous methodologies are being developed. Natural ingredients are being used as nanoformulations and act as an efficient delivery system for the skin. These new generation nanoformulations have improved stability, drug delivery, and showed strong interactions [10] and lipid nanoparticles showed a controlled drug release pattern [11]. The natural nanomaterial (NM) loaded topical formulations are acceptable for topical delivery and offer a safer alternative with good efficacy for the treatment of diseases [10]. Different types of injectable nanoparticles have come on the market such as liposomes, polymeric nanoparticles, micelles, albumin, and a coreshell nanoparticle that avoids excessive drug circulation. Because of their ability to entrap both lipophilic and hydrophilic drugs, nanoformulations loaded with drugs should carry a large number of drugs for UVB-induced skin cancer [12]. Drug delivery nanocarriers such as nanoemulsions, microemulsions, SLN, NLC, liposomes, and niosomes have the advantages of controlled and sustained drug release, site specific targeting, high stability, and penetration power [5]. The properties of nanoparticles affect the skin permeation such as size, shape, coating, toxicity, and purity, and they are efficiently transported to the blood vessels through intercellular and transappendageal routes. Liposomes can be taken orally or applied topically. Liposomes can attain optimum therapeutic efficacy by continuous release of bioactive components, whereas the efficacy of NLCs is dependent on the temperature, percentage of oil incorporated into the lipid layer and the composition of the emulsifier [13].

Figure 1: Pictorial presentation of various properties and beneficial roles of cyanobacterial nanoformulations for skin care. [Click here to view]

3. CYANOBACTERIA UNIQUENESS FOR THE NANOFORMULATIONS SYNTHESIS

In recent years, synthesis of nanoparticles using cyanobacteria has become a growing area of interest due to its wide applications in the field of biomedical sciences. Furthermore, it is economical and environment-friendly. Several cyanobacterial genera have been investigated as a possible resource for the synthesis of nanoparticles. Several cyanobacterial species have been used to synthesize nanoparticles such as Anabaena, Plectonema boryanum, Spirulina platensis, Lyngbya majuscula, Calothrix spp., S. platensis, Phormidium valderianum, and Microcoleus chthonoplastes. The gold nanoparticles were synthesized using P. Boryanum [14]. Some scientists report the production of metal nanoparticles from the culture supernatant [15]. The extract, containing bioactive compounds, helped in the stabilization of the nanoparticles [16]. Silver nanoparticles have been made by N2-fixing cyanobacterium [17], whereas; the gold nanoparticles have been synthesized using S. Platensis [18]. To make nanoparticles, phycoerythrin is extracted from Phormidium tenue and combined with cadmium sulfide. Mycosporine-like amino acids (MAAs) and scytonemin formed the conjugated nanoparticles [16,19]. Hence, cyanobacteria could be used for the synthesis of metal nanoparticles. Zinc oxide nanoparticles (ZnONPs) in conjugation with MAAs have been synthesized to reduce free radicals and improve UV protective activity [19]. Another MAAs shinorine extracted from Anabaena strain L31 conjugated with ZnONPs also showed a reduction in reactive oxygen species (ROS). ZnONPs-shinorine conjugate is collectively used as a biological sunscreen. They are ecofriendly. Scytonemin and other MAAs are also used as photoprotectants as well as antioxidants [20,21]. Scytonema sp. showed antibacterial activity against human pathogenic bacteria, suggesting that it could be a promising treatment option for microbial skin infections [6,22].

4. CHARACTERIZATION OF NANOFORMULATIONS

Nanoformulations have been given tremendous consideration as quickly developing materials for an assortment of uses. Investigation of nanoparticles is a difficult task because of its versatile nature, lacking reference sources for the standardization of tools, sample preparation, estimate of their concentration, and explanation of the data. Nanoparticles can be characterized using different techniques. Nanoparticles were characterized on the basis of particle dispersion, distribution, shape, surface properties, and crystalline. The single property of nanoparticles can be assessed by more than one technique. The size distribution of nanoparticles is an important aspect in maintaining the relationship between the structure and materials that are utilized in nanoparticles, and this can be assessed by the dynamic light scattering technique and electron microscopy. Scanning electron microscopy is a technique that examines the surface of a sample and produces an image through a beam of electrons. Similarly, in transmission electron microscopy an electron beam is transmitted through the sample and produces an image. The sample section should be ultra thin, or less than 100 nm thick, and then the image is magnified and focused on the photographic plate. Atomic force microscopy generates images by the interaction between the probe and sample. This measures the mechanical properties of a sample, like stiffness [23]. Dynamic light scattering is the general method of analysis of the hydrodynamic particle size and distribution over a range of sizes, dependent on Brownian motion and correlated with the velocity and size of the particle using the Stokese Einstein equation. The size of nanoparticles is depicted as the poly dispersity index. Dispersity is the major limiting factor and, thus, there needs to be an accurate size determination [23]. Infrared spectroscopy (IR spectroscopy or vibrational spectroscopy) gives data on the absorption, emission, and reflection of infrared radiation interactions with molecular species. It determines the functional groups in solid, liquid, and as well as gaseous forms [24]. In nanoparticles, different ligands attached may be easily identified [25]. Circular Dichorism spectroscopy is used when we make hybrid nanoparticles, that is, the aggregation of nanoparticles with photosensitizer molecules. It is basically used in organic/inorganic hybrid nanoparticles. This new creation must create new challenges. The fundamental need is to determine the presence of these aggregates [26].

5. VARIOUS TYPES OF CYANOBACTERIAL FORMULATIONS USED FOR SKIN CARE

6. RECENT PATHS OF PROTECTION FROM CYANOBACTERIA

Cyanobacteria are the most primitive organism on earth, and they depend on solar radiation for their normal life cycle. Increased solar radiation causes serious damaged to various physiological and biochemical process in the cyanobacteria. UV radiation caused direct effects by damaging the DNA or indirectly by producing ROS. To combat UV radiation, cyanobacteria developed various protective mechanisms like production of antioxidants, UV protective compounds such as MAAs, scytonemin, and protein resynthesis as shown in Figure 2.

6.1. Role of Cyanobacteria in Photoprotection

The level of anthropogenic chemical has increased due to ozone depletion this give rise to a serious issue with harmful effects on the earth’s ecosystem [43]. Cyanobacteria are more susceptible to UV stress; therefore, various UV protective mechanisms have been developed against the damaging effects of UV radiation on cyanobacterial cells. Various physiological and biochemical processes are effected either directly or indirectly [44]. Cyanobacteria in response to ROS generation produced protective and adaptive mechanisms by regulating gene expression in a variety of cellular signalling pathways. They produce antioxidants such as superoxide dismutase, catalase, and peroxidase which convert ROS into nontoxic products. UV radiation causes breakage in the DNA and lipid peroxidation. Exopolysacchrides is outer layer plays a significant role in providing protection in cyanobacteria against UVR. They have the ability to fix the damaged DNA and protect it against lipid peroxidation by removing ROS produced due to UV radiation [45,46]. UV protecting compounds MAAs and scytonemin produced by cyanobacteria have the ability to reduced toxicity. UV induced DNA lesions in cyanobacteria can be repaired through a variety of methods like photo, excision, recombination, and repair mechanisms. In cyanobacteria, the SOS response and apoptosis have a role in stress tolerance. It was reported that P. Murrayi grew linearly as UV-A levels increased and the UV-B inhibition balanced the damage and repair process when grown under white light and in combination with UV-A and UV-B [47]. Collectively, it appears that cyanobacteria have a stress tolerance mechanism that makes cyanobacteria the most ecologically successful prokaryotes on the planet.

Figure 2: Effects of ultraviolet radiation on skin and multiple defence mechanism system developed by cyanobacteria against the damaging effect of UV. [Click here to view]

Table 1: Various cyanobacterial marketed formulation used for skin care. [Click here to view]

6.3. Role of Cyanobacteria in Inducing Apoptosis

Abiotic (nutrient, light, temperature) and biotic (virus, bacterial, and fungal infection) stress in cyanobacteria due to generated cell death mechanisms [51]. Morphological changes, cell shrinkage, thylakoid degradation, vacuole formation in the cytoplasm, decreased ATP content, photosynthetic activity, and mitochondrial membrane disruption. Caspase-3 like activities is also a hallmark of cyanobacterial apoptosis. UV-induced apoptosis results in direct DNA damage (intrinsic), death receptor clustering on the cell surface (extrinsic), and the production of ROS [52]. Cyanobacterial filaments exposed to UV radiation cells were damaged, filament breakdown, degradation of proteins [51,52]. In the intrinsic pathway of apoptosis, heat shock protein expression plays a significant role in DNA repair mechanisms. Scytonemin pigment extracted from cyanobacteria is responsible for autophagic cell death by increasing ROS, forming multiple vacuoles and DNA fragmentation [50].

Table 2: Experimental techniques for the characterization of nanoformulations. [Click here to view]

7. THE ADVANTAGE OF USING NANOFORMULATIONS FOR SKIN CARE

Current advancements in nanomedicine have occurred in the technological advancements in the distribution and delivery methods of drugs, as well as new methods of diagnosis. The efficacy of drug delivery has increased through formulated drugs with metals together with various nanovehicles such as solid lipid, liquid lipid, and liposomes. Novel natural biomaterials have remained in high demand due to their lower cytotoxic activity, being easily recyclable, and easily available [53]. Through crosslinking techniques, researchers have been able to make natural biomolecules more stable. Hence, polymeric nanoparticles have also been widely in use. Recently, integration therapy has been used to detect cancer like a natural biopolymer conjugated with metal nanoparticles for the detection methods. Nanotechnology available in the cosmetics is the latest area of research. Cosmetic companies use NMs for enhanced UV protection, improved skin penetration, and texture. Micellar nanoparticle-containing cosmetics are becoming increasingly popular in both domestic and international markets [54]. Small micelles formed from nanoemulsion have a high surface area, allowing bioactive compounds to be actively transported into the skin. Nanoemulsion was used extensively in a variety of cosmetic products [55]. Nanoscale emulsions have sparked a lot of interest in recent decades due to their unique characteristics, such as high reliability, esthetic appearance, and high efficiency. Hence, it has been widely used as a minute droplet size in cosmetics [56]. Micellar nanoparticles contain a hydrophobic head and a hydrophilic tail, formed from the aggregation of surfactant molecules. They are formed to encapsulate the hydrophobic drug [53,54]. Micellar nanoemulsion-based cosmetics have been in great demand due to their potential to deliver the bioactive compounds efficiently. They also possess good penetration power to deliver on the skin quickly. Low and high energy techniques have been used to form micelles in nanoemulsion systems [54]. The Malaysian brand contains the micellar nanoparticle in the cosmetic. They launched various cosmetic products such as cleanser and mist. In addition, Loreal, a French cosmetic company, received two patents to form micellar-based cosmetics [54].

8. POSSIBILITIES AND FACTS RELATED TO NANO-FORMULATED DRUG DEVELOPMENT

Microorganisms can be used to make a variety of inorganic and organic nanoparticles. Inorganic nanoparticles have low cytotoxic activity, are hydrophilic and highly stable as compared to organic nanoparticles. Magnetic nanoparticles come under inorganic nanoparticles [53]. Nanoparticles are good targets for drug delivery because of their biocompatibility, ease of preparation on a large-scale, ease of use, and functional efficiency. Nanoparticles are used in a variety of industries, including cosmeceuticals and pharmaceuticals. Nanotechnology offers the fastest platform for developing nanoformulations [57].

Many researchers have developed safe nonmaterials using metals, lipids, polysaccharides, proteins, peptides, and natural products for therapeutics [58]. The bioavailability, stability, and solubility of nanoformulations have resulted in larger particle sizes and larger surface areas. In addition, they can be used in the treatment and diagnosis of biological systems, as well as in the monitoring and management of them. In recent years, cyanobacterial derived nanoformulations have been reported. Nanoformulation derived from cyanobacteria is a growing area of concern [59]. Thus, bioactive compounds found in cyanobacteria have been used for the synthesis of nanoparticles with a wide variety of biomedical applications. Recently, a huge demand for marine natural resources has been used in nanotechnology [59]. Cyanobacteria contain macromolecules such as proteins, amino acids, poysacchrides, vitamins, and minerals [55]. Cyanobacteria have applications in the food and medicine industries. However, there is a scarcity of published data on the production of nano-formulated medicines from microalgal resources. Pharmaceutical and cosmetic companies need to produce a variety of effective nanoformulations for skin health care [37]. Cyanobacterial bioactive and UV protective compounds have been formulated into anti-ageing, antioxidant, and anti-inflammatory creams [39,42]. The microalgal species that contain anticancer compounds have been used by pharmaceutical companies for commercialization. Some aquatic members of green algae, brown algae, red algae, blue green algae, have taken major steps forward in skin cancer treatment, but only a few types of algal nanoformulations are available commercially [60]. Non-melanoma skin cancer incidences have increased in recent years; use of sunscreen is an effective nanocarrier in this case. For example, MAAs and scytonemin loaded nanoformulations have been used to protect against UV radiation and are ultimately used in the treatment of skin cancer [61].

9. MARKET REGULATION AND THE REALITY OF NANOFORMULATED PRODUCTS

NM-based cosmetics have certain distinct advantages as compared to micro-scale cosmetics. The cosmetic industry uses NMs to achieve long-lasting effects and enhanced stability. NMs have a large surface area, which enables more efficient substance delivery through the skin. The efficient penetration into the skin for increased delivery of the product’s ingredients, new color elements, transparency, and long-lasting effects are some of the key goals of employing NMs in cosmetics. When it comes to cosmetics, the ultimate goal is to make us look good [64,65]. The unique feature of NMs that have been present in cosmetic products gives rise to a serious issue, regarding the health of consumers. For this, a standard safety evaluation is necessary, such as the penetration into viable skin layers as well as inhalation [66]. Nanoformulations should be evaluated on the basis of physicochemical features such as aggregate, size distribution, shape, solubility, density, porosity, stability, and contaminants [67]. Cosmetic products should have validated efficacy as well as a rigorous safety investigation. A number of alternatives have been developed, like 2D cell culture models to reduce and bock the anti-inflammation and predict skin sensitization potency, whereas 3D human skin equivalent models have been developed to evaluate common skin dermatitis, and dermal absorption [68]. In European countries, there are certain NMs for example, colloidal silver, styrene acrylate polymer, and sillicates for which the Scientific Committee on Consumer Safety (SCCS) has expressed different opinions due to a lack of information regarding their toxicities [67]. Sprays and powders containing nanoparticles develop a platform for aerosol delivery, so precaution needs to be taken because inhalation can occur. The SCCS guidelines 1602/18 select a list of parameters that are required for an exposure [67]. NM concentrations are given in terms of weight, particle number and surface area and also, in the form of any accumulation, disintegration and dissipation are reported during exposure. Besides NMs in contact with skin, NMs are also present in toothpastes, mouthwashes, and lipsticks [67].

10. CONCLUDING REMARKS AND FUTURE PERSPECTIVES

Various bioactive compounds, including antioxidants, carotenoids, UV protective pigments, polysaccharides, steroids, have been present in cyanobacteria with wide application in pharmaceuticals, nutraceuticals, and biomedical. Certainly, our understanding of algal bioactive compounds regarding NMs has improved, but still more emphasis is needed on their use as medicine and commercialization needed. Nanoformulations containing cyanobacterial secondary metabolites have the potential to enhance UV radiation protection mechanisms, which will contribute to the advancement of skin health care.

In the review, we highlighted the lack of studies and commercialization using microalgal bioactive compounds for drug development. Furthermore, additional technologies and knowledge are required to investigate the efficacy of secondary metabolites to formulate the nanoformulations. A Cyanobacterial nanoformulation uses nano-fusion technology and green technology for drug development. Large scale production and cost effectiveness should be a major task to make cyanobacterial loaded nanoformulation. Novel functions of cyanobacterial secondary metabolites need to be explored.

11. ACKNOWLEDGMENT

The authors acknowledge the Life Science Research Board (LSRB) Defense Research and Development Organization for providing the financial assistance and the Office of Doctoral Studies and Research for critically reviewing the manuscript and providing the manuscript number (IU/R&D/2021-MCN0001075).

12. CONFLICT OF INTERESTS

The authors declare no conflict of interests, financial, or otherwise.

13. FUNDING

This work was financially supported by the Life Science Research Board (LSRB) Defense Research and Development Organization (Project No.LSRB-293/SH&DD/2017).

14. ETHICAL APPROVALS

Not applicable.

15. DATA AVAILABILITY

All data generated and analyzed have been included in this article.

16. PUBLISHER’S NOTE

This journal remains neutral with regard to jurisdictional claims in published institutional affiliation.

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