Ultradeformable Vesicles for Wound Healing: Ethosomes, Transferosomes, and Transethosomes in Topical Drug Delivery.

Wound healing is a dynamic and multifaceted biological process involving hemostasis, inflammation, proliferation, and tissue remodeling. Topical therapy is widely preferred for wound management due to its localized action and reduced systemic adverse effects. However, the effective delivery of therapeutic agents is often limited by the skin's barrier properties, the complex wound microenvironment, and the physicochemical characteristics of drugs. This review highlights the key physicochemical parameters governing topical drug delivery in wound therapy, including drug solubility, molecular size, lipophilicity, vesicle size distribution, surface charge, encapsulation efficiency, lipid composition, ethanol concentration, and vesicle deformability, which collectively influence drug permeation and retention at the wound site. Nanovesicular delivery systems have emerged as promising strategies to overcome these limitations. In particular, ultradeformable vesicles such as ethosomes, transferosomes, and transethosomes have demonstrated enhanced skin permeation and improved drug deposition in periwound tissue due to their flexible membrane structure and optimized physicochemical properties. This review systematically discusses the composition, preparation techniques, and critical formulation parameters of these vesicular systems that determine their stability, elasticity, and permeation performance. Furthermore, their applications in delivering anti-inflammatory drugs, antimicrobial agents, bioactive phytochemicals, and regenerative therapeutics for different wound types are examined. Widely used in vitro, ex vivo, and in vivo evaluation methods, including permeation studies and wound healing models such as excision, burn, infected, and diabetic wounds, are also summarized. Finally, the review outlines current challenges related to formulation standardization, physicochemical characterization, safety assessment, and large-scale production, while highlighting the future potential of ultradeformable vesicles as next-generation nanocarriers for advanced wound healing therapies.