Transfersomes and Ethosomes for Enhanced Transdermal Drug Delivery: Mechanistic Insights and Comparative Evaluation

Transdermal drug delivery systems (TDDS) provide a non-invasive alternative to conventional dosing but are often restricted by the skin’s primary barrier, the stratum corneum. This review evaluates second- and third-generation ultradeformable vesicles—transfersomes and ethosomes—designed to overcome these limitations. Transfersomes utilize edge activators to achieve extreme elasticity, allowing them to squeeze through narrow pores via a transdermal osmotic gradient. Conversely, ethosomes leverage high ethanol concentrations to fluidize skin lipids, facilitating deep penetration through a "push-pull" mechanism. The review compares their composition, mechanisms, and applications in delivering diverse therapeutic agents, including proteins and lipophilic drugs. While challenges such as physical instability and regulatory hurdles remain, emerging hybrid systems like transethosomes and integration with microneedles represent the future of efficient, localized, and systemic transdermal therapy.