Invasomes: A smart nanovesicular platform for enhanced transdermal drug delivery

Transdermal drug delivery systems (TDDS) provide a non-invasive alternative to oral and injectable administration; however, their clinical utility remains limited by the formidable barrier properties of the stratum corneum, which restrict the delivery of many therapeutic agents, particularly hydrophilic and high-molecular-weight molecules. Invasomes, composed of phospholipids, ethanol, and terpenes, have emerged as highly deformable nanovesicular carriers capable of enhancing skin permeation through synergistic lipid fluidization and vesicular flexibility. This review provides a comprehensive and updated overview of invasome-based transdermal drug delivery, distinguishing itself from previous reviews by integrating recent advances in formulation strategies, physicochemical characterization, penetration mechanisms, therapeutic applications, smart and hybrid invasomes, computational formulation design, regulatory considerations, and translational challenges. The review critically discusses the influence of formulation variables, including phospholipid composition, ethanol content, terpene type, and drug physicochemical properties, on vesicle characteristics, stability, encapsulation efficiency, and biological performance. Furthermore, recent in vitro, ex vivo, and in vivo studies collectively demonstrate that invasomes significantly enhance skin permeation, drug deposition, bioavailability, and therapeutic efficacy compared with conventional vesicular systems while maintaining favorable safety profiles. Emerging innovations, including stimuli-responsive invasomes, microneedle-assisted delivery, artificial intelligence-guided formulation optimization, and molecular modeling, are also highlighted as promising approaches for next-generation transdermal therapies. Despite encouraging preclinical evidence, challenges related to large-scale manufacturing, long-term stability, regulatory standardization, and clinical validation remain to be addressed. Overall, this review provides a current and translational perspective on invasome technology and highlights its potential as a versatile nanovesicular platform for future clinical transdermal drug delivery.