Heat-Responsive Phase-Change Cream Broadly Enhances Transdermal Delivery Through a Mild Photothermal Strategy.

High-temperature-mediated transdermal delivery often relies on extreme heating to disrupt the skin barrier, but these approaches risk tissue damage and drug denaturation. Mild thermal stimulation promises safer uptake, yet achieving precise temperature control is inconvenient, and its transdermal efficacy and mechanisms remain unclear. A heat-responsive cream made from a stearic acid-lauric acid eutectic, polydopamine (PDA) nanoparticles, glycerin, and drugs is introduced. This cream maintains skin temperature ∼40 °C under simulated sunlight by absorbing excess heat through phase change, preventing overheating while preserving the effectiveness of the drug without requiring manual adjustments. Mild photothermal treatment boosted penetration of PDA nanoparticles (2.4-406.9 nm) by 5.5-7.1-fold, and achieved 28.9-, 24.6-, and 10.7-fold increase of fluorescent signals in dermis for rhodamine B (RB), RB-labeled 5 or 20 kDa dextran versus nonheated controls, respectively. Mechanistic studies revealed that the photothermal effect enhances transdermal delivery by inducing micropores on the skin and through the transappendageal route. Moreover, insulin delivered through this strategy reduced blood glucose by 75% in diabetic mice, and co-delivery of PDA NPs with methotrexate significantly improved psoriasis lesions. This self-regulating platform uniquely unites precise thermal control and dual-pathway enhancement, offering a generalizable route for enhancing transdermal delivery efficiency.