From Barrier Disruption to Precision Skin Interface Engineering: Next-Generation Transdermal Drug Delivery.

Transdermal drug delivery (TDD) is reemerging as a clinically attractive route for noninvasive therapy, driven by the growing demand for alternatives to repeated injection and by the rapid development of materials capable of regulating transport across the skin. By avoiding gastrointestinal degradation and hepatic first-pass metabolism, TDD can provide prolonged drug exposure, reduce peak-to-trough fluctuations in plasma concentration, and improve adherence in long-term treatment. Its broader implementation, however, is still constrained by the exceptional barrier function of the stratum corneum, which severely limits the passive transport of hydrophilic molecules, charged species, and macromolecular therapeutics. In this review, we critically discuss the structural basis of the skin barrier and summarize the evolution of TDD strategies from conventional chemical permeation enhancement and device-assisted physical disruption to nanocarrier-mediated, biomimetic, and intelligent bio-delivery systems. Particular emphasis is placed on the mechanistic logic that connects carrier composition, interfacial interactions, skin microenvironment remodeling, and therapeutic performance. Representative examples are analyzed to highlight both opportunities and translational bottlenecks. Finally, we outline future directions in multimodal delivery, pathology-adapted design, standardized evaluation, and scalable manufacturing, which will be essential for transforming TDD from a permeability enhancement technology into a precision-regulated therapeutic platform.