Polymeric micelles, or aggregation colloids generated in solution by the self-assembly of amphiphilic polymers, are a novel method for overcoming a variety of drug delivery difficulties, ranging from low water solubility to poor drug permeability through biological barriers.

Amphiphilic di-block copolymers (polystyrene and poly (ethylene glycol)) and triblock copolymers (poloxamers) are the most widely utilized polymers for micelles production, although graft (e.g. chitosan) and ionic (poly (ethylene glycol)) polymers are also employed (ethylene glycol) The copolymers–poly (-caprolactone)-g-polyethyleneimine) are utilized. The hydrophilic segment is usually made of PEG (polyethylenglycol), but other polymers such as poly (vinyl pyrrolidone), poly (acryloylmorpholine), or poly (trimethylene carbonate) can also be used; the hydrophobic segment can be made of poly (propylene oxide), polyesters like poly (-caprolactone), or glycolic and lactic acid polymers and co-polymers (Mandal et al., 2017). Among all of these options for joining hydrophobic and hydrophilic blocks to generate amphiphilic polymers, attaching phosphatidyl ethanolamine (PE) to the hydrophilic PEG is a comparatively easy technique that only requires one conjugation step between amine or acid terminated PE. The synthesis has good structural control, has a good lipophilic hydrophilic balance, is chemically stable, biocompatible, and biodegradable. Other block co-polymeric assemblages have more structural flexibility and can hold more drugs (Logie et al., 2014).

Depending on the technique of manufacture and the physicochemical features of the medication, protein can be encapsulated in the micelles during their creation or in a subsequent stage. Direct dissolving is the most straightforward way of preparation; additional options include dialysis, emulsion with solvent (or co-solvent) evaporation, and solution-casting followed by film hydration. The choice of approach is based on both polymer and drug features, and further information may be obtained in specific reviews (Makhmalzade and Chavoshy, 2018). Because micelle features such as polarity and hydration degree are not uniform inside the carrier, the medication can be housed in a variety of locations, such as near the surface or deep within the carrier, depending on its qualities. Hydrophobic medicines are usually loaded and stored in the inner core.

Polymeric micelles are attractive carriers for many administration routes due to their small size, ease of synthesis, and good solubilization capabilities. Micelles are thermodynamically self-assembled entities with reversible limits that may be disassembled by a variety of destabilizing forces. Micelles must deal with varied challenges depending on the route of administration; the behavior of the micelles is then determined by their composition and general features, such as size, surface charge, shape, thermodynamic and kinetic stability. All of these properties are crucial in determining the micelle’s destiny and, as a result, drug bioavailability.

Polymeric micelles offer a number of characteristics that make them a viable protein delivery platform. In comparison to lipid-based vesicles, they are nano-sized, monodispersed, reasonably stable, and cost-effective, and they may be surface-modified or stimuli-sensitized by changing their chemical structure. Many amphiphilic polymers have been produced and studied for their capacity to self-assemble and load poorly soluble proteic drugs throughout the years due to their lower size compared to other lipid carriers. The creation of the amphiphilic polymer has been connected to various combinations of hydrophobic and hydrophilic polymeric building units.

Hydrophobic protein might be loaded into the center of polymeric micelles. The physical interaction between the proteins and the polymers, on the other hand, governs the trapping of proteins in the micelles’ core. As a result, a variety of options for conjugating hydrophobic and hydrophilic blocks have evolved in order to develop a better micellar system capable of loading a specific chemotherapeutic drug optimally. The options for conjugating polymeric blocks are limitless, and many different combinations have been tested in recent years.

Lipid-based nanocarriers are effective drug delivery nanosystems. The remarkable qualities of their lipid components, such as high flexibility, biocompatibility, and low toxicity profile, have drew a lot of attention to these nanocarriers in recent decades. Lipid-based nanocarriers can be used to improve the therapeutic potential of medications with biopharmaceutical constraints, such as limited water solubility or stability, as well as to provide alternatives to the parent route.

Liposomes, self-nano and microemulsifying drug delivery systems, nanoemulsions, and nanocapsules are all examples of lipid-based nanocarriers. They all have in common the ability to alter their formulation to the features and requirements of the oral route. Indeed, the majority of the oils and fats employed in the production of these nanocarriers are derived from dietary lipids, allowing for improved oral permeability and biodegradability. Furthermore, lipid-based nanocarriers may be engineered to interface with particular cell populations in the gastrointestinal system, boosting medication delivery effectiveness (Ghorbanzade et al., 2017; Plaza et al., 2021).

Liposomes are spherical vesicles made up of one or more lipid bilayers made up of natural or manufactured phospholipids that form lipid bilayer spheres in water and encase aqueous nuclei. Phospholipid molecules and cholesterol with mixed lipid chains (such as phosphatidylcholine from soybeans or phosphatidylethanolamine from eggs) can be found in liposomes (Colletier et al., 2002; Liu et al., 2020). Amphiphilicity of phospholipids is responsible for the production of vesicles in aqueous solutions, which are stabilized by hydrogen bonds, van der Waals forces, and electrostatic interactions (Sercombe et al., 2015; Pattni et al., 2015).

Liposomes come in a variety of sizes, ranging from 20 nm to several micrometers, and are commonly employed as biomembrane models and biocompatible delivery methods (Zarrabi et al., 2020). Liposomes are tiny bilayer vesicles that come in a variety of sizes and forms. They’re lipid layer vesicles that enclose an aqueous phase.

Liposomes may be classified into several kinds based on their fabrication technique, which may include one or multiple bilayer shells (Figure 3). Liposomes are divided into four types based on their structure: multilamellar vesicles (MLVs, 0.1–15 mm), small unilamellar vesicles (SUVs, 15–50 nm), large unilamellar vesicles (LUVs, 100–1 mm), and multivesicular vesicles (MVVs, 1.6–10.5 mm), OLVs are oligolamellar vesicles (OLVs) having a diameter of 100–1,000 nm. A liposome with an aqueous phase enclosed by a bilayer structure is known as a unilamellar liposome. The quantity of aqueous phase contained in each mole of lipid rises as particle size increases, and stability improves (Doskocz et al., 2020; Liu et al., 2020). Static and dynamic light scattering (DLS), microscopy, size exclusion chromatography (SEC), field flow fractionation (FFF), and centrifugal analysis are used to evaluate the size distribution of liposomes. Electron microscopy or spectroscopic technologies can be used to examine the multilayer structure of liposomes (Waglewska et al., 2020).

Because of their advantages such as lipophilic/hydrophilic properties, ability to compartmentalize space, and flexible colloidal sizes, liposomes have been widely used to entrap various compounds such as peptides (Mohan et al., 2016), enzymes (Jahadi et al., 2015), antioxidants (Tavakoli et al., 2018), antimicrobials (Cui et al., 2017), essential fatty acids (Faridi Esfanjani et al., 2018).

The ratio of the substance encapsulated in the liposomes to the total amount of compound at the initial input is known as encapsulation efficiency. It is dependent on the liposome’s capacity to capture the encapsulated molecules as well as the number of encapsulated molecules’ starting moles. Depending on their solubility and polarity, encapsulated compounds interact with liposomes in a variety of ways. They can be completely trapped in the lipid chain’s bilayer area, interspersed in the polar head group region, adsorbed on the membrane surface with a hydrophobic tail, or imprisoned in the interior aqueous compartment (Gomez and Hosseinidoust, 2020). Dilution with alcohol, extraction of lipids in a chloroform solution, or forced bilayer breakdown by surfactants are all common methods for determining the quantity of substances contained in liposomes, with subsequent measurement of release (Tomadoni et al., 2019; Amarachinta et al., 2021).

Quantitative approaches such as spectrophotometry, fluorescence spectrometry, enzymatic methods and electrochemical methods are all dependent on the liposome vesicle’s characteristics (Gerente et al., 2007).

Liposomes are a good way to preserve labile molecules like enzymes from degradation while yet allowing them to function effectively. It’s a very effective approach for physically immobilizing enzymes, which makes them more stable and allows them to be introduced into cell membranes with regulated release of active principles (Mikhaylov et al., 2011).

Enzymes, peptides, and nanoparticles may now be encapsulated within liposomes thanks to advances in entrapment techniques. Encapsulation techniques preserve enzyme function by preserving it from denaturation caused by pH extremes, high temperatures, and protease action (Ngo et al., 2010).

Liposomes’ physical, chemical, and biological stability are only a few of the issues that restrict their use. Dimensional stability, lipid-to-substance ratio, and entrapped membrane are all examples of physical stability. Liposomes’ physical stability can be enhanced by storing them at low temperatures (Babaki et al., 2016). Liposomes are typically stable for minutes to weeks. Using specific procedures, however, liposomes may be bonded to be stable for extended periods of time. Tan et al. (2016), for example, found that unilamellar liposomes produced by the emulsion transfer method can last up to 26 days. The hydrolysis and oxidation of lipids are the primary causes of chemical instability. It’s also brought on by the digestion of catabolic enzymes. Hydrolysis is used to eliminate fatty acid residues. Oxidation also has an impact on unsaturated lipids. The biological stability of liposomes is now a hot issue; for example, it is affected by the type of lipids used to create the liposomes, as well as polymerization and interactions with other components. Optical techniques based on solute leakage from liposomes have been used to evaluate membrane mobility and penetrability using common fluorescent probes (Mendes et al., 2011). Chen et al. (2017) used changes in the Z-average diameter and retention rate to assess the stability of liposomes loaded with b-ionone after storage at 4°C.

Traditional liposomes are commonly used to immobilize enzymes and increase their stability for storage or usage. Encapsulation in liposomes, on the other hand, can reduce the bioavailability of encapsulated enzymes (Nguyen et al., 2016).

As a result, numerous attempts have been undertaken to alter the outer membrane of liposomes in order to improve their stability and permeability, with the goal of developing innovative uses as a result (Kim et al., 2014).

The ethosomes are elastomeric nanovesicles made of phospholipids with a high ethanol concentration (20–45%). (Waglewska et al., 2020). Both hydrophilic and hydrophobic components can be encapsulated in these easily produced lipid vesicles. Essential oils may be integrated into ethosomes by dissolving them in ethanol with great flexibility and entrapment efficiency because ethosomes have a shell of bilayer phospholipids and a core of ethanol phase. Because of ethanol evaporation, the fundamental disadvantage of ethosomes is their limited stability. Because of their increased permeability qualities, most of the current literature on the application of essential oils loaded ethosomes is in the field of topical distribution. This is owing to their high fluidity, which is attributable to the synergistic impact of phospholipids and ethanol. Ethanol is a permeation enhancer that has been used to make these elastic nanovesicles in vesicular systems. These ethosomal systems are more effective in releasing chemicals to the skin than liposomes or traditional hydroalcoholic solutions. Ethosomes are efficient in transporting chemicals into the bloodstream. It’s been utilized to deliver the antiviral medication acyclovir via the skin. Because of their superior water solubility and biocompatibility, ethosomal gels are used with medicines. (Ascenso et al., 2015; Yücel et al., 2019).

Ethosomes are non-invasive delivery carriers that allow medications to reach deep into the epidermal layers or the systemic circulation (Kumar et al., 2020). They offer outstanding features such as room-temperature stability, high entrapment efficiency, and compatibility with the stratum corneum, which allows for efficient release of hydrophilic and lipophilic medicines into the deep layers of the skin (Abdulbaqi et al., 2016; Xiao-Qian et al., 2019). According to their composition, ethosomals systems may be divided into three groups:

• Phospholipids, a high concentration of ethanol (45%), and water make up traditional ethosomes.

Transfersomes, also known as elastic, deformable, or ultra-flexible liposomes, were first reported by Cevc and Blume (1992). Their characteristics make them excellent transdermal medication delivery devices (TDDS). Due to their ultra-deforming membrane, drugs are easily administered into or through the skin, squeezing themselves along the intracellular lipid or transcellular channel of the stratum corneum. Furthermore, owing of their flexibility, they have a lower risk of skin rupture, and this trait also allows them to follow the natural water gradient across the epidermis under no occlusive circumstances (Opatha et al., 2020).

Transfersomes hydrophobic and hydrophilic compositions allow them to transport medications of various solubilities while being extremely biocompatible owing to their inherent phospholipid content (Manconi et al., 2019). They may also contain low or high molecular weight medicines, with an entrapment effectiveness of up to 90% (Abdellatif and Abou-Taleb, 2016). These structures also have the advantages of being resistant to metabolic breakdown and releasing their contents slowly and gradually. However, transfersomes have some drawbacks, such as oxidative deterioration and the challenge of transporting hydrophobic medicines without affecting their elastic and deformability features (Harmita et al., 2020).

Niosomes are non-ionic surfactant vesicles that are formed by hydrating synthetic non-ionic surfactants with or without cholesterol or lipids (Patra et al., 2018). These are generated by non-ionic surfactant self-assembly in non-aqueous fluids as spherical, multilamellar, and polyhedral structures, as well as inverse forms that only emerge in aqueous solvent. A variety of non-ionic surfactants have been utilized to produce vesicles since then. Polyglycerol alkyl ethers, glucosyldialkyl ethers, crown ethers, polyoxyethylene alkyl ethers, ester linked surfactants and steroid linked surfactants (Zhu et al., 2018).

Niosomes are a handy, long-lasting, targeted, and effective medicine delivery mechanism. They may be used to encapsulate a variety of natural active compounds, such as enzymes and peptides. These vehicles, unlike liposomes, have a unique structure that permits them to transport both hydrophilic and lipophilic medications, making them a viable drug delivery option (Manosroi et al., 2016).

Niosomes are biocompatible, biodegradable, and long-lasting, allowing for controlled and sustained drug administration to the target site (Habib and Singh, 2021). Papain is a proteolytic enzyme that is generated from the latex of the Carica papaya plant and is used to repair wounds. Despite this, the enormous molecular weight of papain makes it challenging to employ topically (Ruslan and Roslan, 2016). They are vesicular structures that look like liposomes and can transport both amphiphilic and lipophilic medicines. Vesicles are defined as little sac-like entities that are made up of or related to. Both niosomes and liposomes have the same medication delivery capacity and boost effectiveness when compared to free drug. Niosomes are chosen over liposomes because they are more chemically stable and cost less. In aqueous environments, non-ionic surfactant vesicles are tiny lamellar structures including spherical, uni or multilamellar, and polyhedral vesicles with sizes ranging from 10–1,000 nm.

The mean diameter of niosomal vesicles is calculated using the laser light scattering technique, and their shape is intended to be spherical. Electron microscopy, optical microscopy, ultracentrifugation, molecular sieve chromatography, photon correlation microscopy, and freeze fracture electron microscopy may all be used to quantify diameter. Under light polarisation microscopy, an X–cross formation is used to quantify bilayer formation. Nuclear magnetic spectroscopy and electron microscopy are used to count the number of lamellae.

Bilosomes (bile salts including niosomes) are a novel type of vesicular carrier that was initially reported by Conacher et al. (2001). Bilosomes are non-ionic amphiphile closed bilayer vesicles that integrate bile salts, similar to niosomes. Several studies have shown that bilosomes may be used to administer vaccinations successfully orally (Aburahma, 2014; Jain et al., 2014). Bile salts in the lipid bilayers of bilosomes make them more resistant to bile salts and enzymes found in the gastro-intestinal (GI), providing protection for the entrapped vaccine from the GI tract’s hostile environment.

In terms of composition, chemical stability, and storage conditions, they differ from liposomes and niosomes. Vaccines based on bilosomes provide a systemic and mucosal immune response that is comparable to the immunological response elicited by the subcutaneous method. When it comes to storage and handling, bilosomes don’t require any specific considerations. Bilosomes have the advantage of allowing little amounts of antigen to be effective while also increasing the efficacy of antigen that is weak initially injected. They are a safe and effective alternative to conventional vaccinations since they do not involve the use of live organisms. This non-invasive technology has a higher acceptability and compliance rate among users.

Vesicular delivery systems are highly organized assemblies made up of one or more concentric bilayers that develop because of amphiphilic building blocks self-assembling in water. These systems are crucial for targeted medication delivery because they have the capacity to localize drug activity to the organ or site of action, lowering concentrations at other parts of the body, the drug delivery systems (DDS) has the ability to maintain drug levels at a preset pace (zero-order kinetics) and maintain effective medication concentration inside the body, therefore reducing adverse effects.

Encapsulation technologies are used to produce controlled-release delivery systems in medicine, pharmaceutics, agriculture, and cosmetics. Drugs, insecticides, perfumes, and enzymes are released over time via colloidal systems including ethosomes, bilosomes, and niosomes. The composition of colloidal particles used to encapsulate enzymes and other proteins determines the properties of the particles. The active principle’s capacity to encapsulate, protect, and distribute the active principle is influenced by the composition of encapsulated systems (Perry and McClements, 2020).

Colloidal vesicles may be made from a variety of edible components, including proteins, polysaccharides, lipids, phospholipids, and surfactants (Aditya et al., 2017). As a result, choosing the best components to build an enclosed system is critical.

For specific applications, the size and shape of the colloidal enzyme-encapsulating vesicles can also be modified. Depending on the components utilized and the manufacturing techniques used to produce them, colloidal particles can range in size from around 10 nm to 1 mm. Colloidal particles are typically spherical, although various morphologies, such as ellipsoid, cubic, fibrous, or irregular, are also conceivable. Emulsions are mixtures of oil (O) and water (W). It is possible to make O/W and W/O emulsions, both of which are appropriate for encapsulation (Niu et al., 2017). As a result, O/W emulsions are used to encapsulate enzymes in oil-filled capsules for oral delivery. This sort of technology is used to preserve bioactive peptides, enzymes, and proteins from digestive enzyme breakdown. The fact that these systems may be made from a variety of natural oils and emulsifiers is their major benefit. W/O emulsions, on the other hand, are more expensive and time-consuming to make. Furthermore, they are unstable, decomposing during storage or when subjected to environmental stressors (Sobczak et al., 2017; Perry and McClements, 2020).