Controlled Delivery of MTX from Thermosensitive Hydrogels Using Au Nanorods for Enhanced Therapeutics of Psoriasis via Improving Stratum Corneum Penetration

Abstract Topical transdermal drug delivery for psoriasis remains a challenge because of the poor solubility of hydrophobic drugs and the limited penetration of the stratum corneum. In this study, a near‐infrared (NIR) light‐responsive thermosensitive hydrogel (PDLLA‐PEG‐PDLLA, PLEL)‐based drug reservoir is developed that directly incorporated gold nanorods (GNRs) and methotrexate (MTX) in the sol state at low temperature, which is referred to as PLEL@GNR+MTX. The in vitro anti‐psoriasis experiment indicated that, GNRs, as photothermal cores of composite hydrogel, not only triggered keratinocyte apoptosis but also promoted MTX release in a synergistic manner. Moreover, the rapid phase transition enhanced the penetration of the hydrogel formulation through the stratum corneum upon NIR light irradiation and prolonged skin retention after returning to a gel state in a psoriasis mouse model. Compared with commercial ointment treatments, the PLEL@GNR+MTX hydrogel have similar efficacy in psoriatic lesion resolution but without skin wrinkling. The prepared hydrogel featured excellent biocompatibility and the accumulation of GNRs in healthy organs and skin tissues is negligible. Overall, the light‐activatable hydrogel‐based platform can utilize NIR as a “trigger switch” to release MTX more precisely, improve bioavailability, and facilitate permeation across the skin barrier during reversible phase‐change processes.