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Exosomes, a category of extracellular vesicle (EV), are phospholipid bilayer structures ranging from 30 to 150 nm, produced by various organisms through the endosomal pathway. Recent studies have established the utilization of exosomes as nanocarriers for drug distribution across various therapeutic areas including cancer, acute liver injury, neuroprotection, oxidative stress, inflammation, etc. The importance of plant-derived exosomes and exosome vesicles derived from mammalian cells or milk, loaded with potent plant bioactives for various therapeutic indications are discussed along with insights into future perspectives. Moreover, this review provides a detailed understanding of exosome biogenesis, their composition, classification, stability of different types of exosomes, and different routes of administration along with the standard techniques used for isolating, purifying, and characterizing exosomes. Plain Language Summary Exosomes are tiny, spherical structures made of two layers of lipids, measuring between 30 and 150 nm in diameter. They are flexible, less harmful to the immune system, can cross barriers in the body, and also can be used as vehicles to carry drugs. Various methods are used to obtain, separate, and purify the exosomes based on their size, shape, density, and specific markers. Exosomes obtained from plants can treat various diseases as they are less toxic, have high permeability, and are environmentally safe. The chemical compounds obtained from plants can be loaded into the exosomes obtained from sources like milk, or human cells both healthy and diseased, having the ability to treat cancer, inflammation, liver diseases, etc. GRAPHICAL ABSTRACT Article highlights Introduction to exosomes Exosomes are small vesicles released by most eukaryotic cells, that facilitate intercellular communication and possess an extended half-life, allowing them to traverse extended distances within the body under both normal and disease conditions. Advantages of exosomes The exceptional drug-delivery potential of exosomes, originating from their less immunogenic, non-cytotoxic, and non-mutagenic ability, surpasses that of liposomes. In advanced medicine, exosomes are investigated as a promising cell-free therapy due to their targeted effects on cells, reduced safety issues, and low manufacturing costs in comparison to cell-based therapies. Challenges with exosomes Human cell-derived exosomes have scalability and scalability challenges associated with the low yield. To address this exosome-derived plants have emerged as a promising alternative. Ethical concerns Researchers must thoroughly evaluate the potential risks associated with exosome-based therapies, including immunogenicity, off-target effects, and long-term complications. Patients should be fully informed about the nature of exosome therapy, including its potential benefits, risks, and uncertainties. In-depth investigation of the animal-derived, and plant-derived exosomes is required before using them for therapeutic interventions. Advantages of plant-derived exosomes Plant-derived exosomes owing to their small size are considered to be environmentally safe, less toxic, and have high permeability; biological functions and pharmacological properties of plant-derived exosomes closely resemble those of their parent plants and often surpass those of isolated plant compounds. Isolation & purification methods The selection of different isolation and purification methods such as ultracentrifugation, size-based separation, polymer-based methods, affinity-based separation, and microfluidic systems are to be taken care of as they can influence the purity and the physiological characteristics of the exosomes. Future perspectives The plant-derived exosomes with their superior advantages of higher yield, widely available, prolonged half-life, and better stability in biological fluids show future potential for treatment strategy and therapeutic intervention. [ABSTRACT FROM AUTHOR]

Transethosomes, a fusion of transferosomes and ethosomes, combine the advantageous attributes of both vesicular systems to enhance deformability and skin permeation. While skin delivery is effective for drug transport, overcoming the skin barrier remains a significant challenge, particularly for plant-based products with poor permeability. Transethosomes offer a promising solution, but their low viscosity and retention on skin surfaces led to the development of transethosomal gels. These gels can entrap unstable and high molecular weight herbal extracts, fractions and bioactive compounds, facilitating enhanced drug delivery to the inner layers of the skin. This review focuses on the superior performance of transethosomes compared with conventional lipid-based nanovesicular systems, offering an advanced approach for transdermal delivery of plant-based drugs with improved permeability and stability. Graphical Abstract Article highlights Transdermal drug delivery is valued for controlled release and avoiding first-pass metabolism. Traditional formulations face challenges due to the skin's barrier, especially the stratum corneum. Transethosomes (TEs) offer a solution by disrupting lipid bilayers and enhancing drug permeation. However, TEs' low viscosity and skin surface retention need improvement. Transethosomal gel formulations combine TEs with a gel matrix, addressing these issues. These gels offer enhanced drug retention and controlled release. They hold promise for various therapeutic applications, but optimization is crucial for efficacy and safety. Properties of transethosomes Transethosomes are a combination of transferosomes and ethosomes. Which is composed of phospholipids, edge activators and ethanol. The flexibility of TEs facilitates penetration through skin lipid bilayers. Allow for the entrapment of high molecular weight, both hydrophilic and lipophilic phytochemical drugs, showing versatility. Mechanism of action of transethosomes Transethosomes penetrate deeper skin layers through two mechanisms: the ethanol impact mechanism and the vesicular mechanism, which involves hydrotaxis and elastomechanics. The ethanol impact mechanism relies on the solvent's ability to disrupt the skin's lipid barrier, facilitating penetration. Meanwhile, the vesicular mechanism utilizes the deformability and elasticity of transethosomes to navigate through the skin's layers, aided by hydration gradients and mechanical forces. Advantages of TEs & TEs gel in drug delivery TEs and TEs gel offers several advantages, including high patient compliance, avoidance of first-pass metabolism, improved bioavailability, high entrapment efficiency and controlled release. These properties make TEs and TEs gel promising candidates for effective transdermal drug delivery. Preparation methods of transethosomes Transethosomes are prepared following different preparation techniques: Solvent Injection Method, Thin-Film Hydration Method, Ethanol Injection Method, Reverse Phase Evaporation Method, Freeze-Thaw Method. Characterization & evaluation of TEs & TEs gel Techniques like particle size analysis, TEM, zeta potential measurement and FTIR spectroscopy provide insights into size, structure, stability and composition, ensuring their quality and effectiveness. The evaluation of transethosomal gel involves assessing its physical properties, drug release kinetics, skin permeation and stability. Techniques such as viscosity measurement, spreadability testing, drug release studies, skin permeation assays and stability testing under various conditions are employed to ensure their suitability for transdermal drug delivery. Optimization of TEs & TEs gel formulations To maximize the potential of TEs and TEs gel, several factors need careful consideration, including stability, purity of phospholipids, loading capacity, entrapment efficiency and formulation methodology. Optimization of these parameters is crucial for ensuring the efficacy and safety of TEs and TEs gel in transdermal drug delivery. Therapeutic applications of TEs gel Various TEs gel formulations, entrapping different plant extracts and bioactive compounds, have demonstrated high lipid solubility and therapeutic efficacy. Applications include pain management, dermatology, treatment of skin cancers, antibacterial therapy and systemic drug delivery. [ABSTRACT FROM AUTHOR]

Invasomes and invasomal gel are ultraflexible, soft vesicular, phospholipid based nanocarriers with deeper skin penetration ability for transdermal applications of drugs and phytopharmaceuticals. [ABSTRACT FROM AUTHOR]