Sprayable androgen receptor PROTAC degrader for immunomodulation and accelerated skin regeneration

Despite extensive pharmacological efforts to apply targeted protein degradation (TPD) across diverse disease contexts, strategies enabling its convenient and practical use remain limited. To expand the therapeutic landscape of TPD, we herein design a proteolysis-targeting chimera (PROTAC) degrader with excellent compatibility in aqueous hydrogels, thereby establishing a sprayable system for dermatological conditions. This sprayable hydrogel allows user-friendly topical application and ensures prolonged skin retention of the PROTAC through robust tissue adhesion. Targeted proteolysis of the androgen receptor (AR) generates a pro-regenerative microenvironment by inducing a macrophage phenotypic shift from the proinflammatory M1 to the anti-inflammatory M2 state. Consequently, topical spraying of the PROTAC-loaded hydrogel accelerates skin regeneration, highlighting its potential as a versatile therapeutic platform for both wound repair and psoriasis management. Extending beyond conventional PROTAC research, which has primarily focused on target identification and chemical optimization, this study introduces a practical design strategy for translating TPD into regenerative medicine.