Polydopamine-loaded prunetin nanomaterials activate DRD2 to reduce UV-induced inflammation by stabilizing and promoting Nrf2 nuclear translocation.

Skin damage caused by exposure to ultraviolet (UV) light has been well documented clinically and histologically. Dopamine receptor D2 (DRD2) possesses various biological functions. However, no study has reported the possible association of DRD2 with UV-induced skin damage. We established DRD2 conditional knockout and UV damage models in this work. The results showed that DRD2 played an important role in the treatment of UV-induced skin damage. The findings of the molecular mechanism study revealed that the internalization of DRD2 after activation can stabilize nuclear factor erythroid 2-related factor 2 (Nrf2). However, the entry of Nrf2 into the nucleus did not increase. We prepared and characterized hyaluronic acid (HA)-coated mesoporous polydopamine (MPDA) nanoparticles (H@P@M). HA facilitated skin epidermal penetration of the nanoparticles to reach the site of inflammation smoothly. Meanwhile, MPDA activated DRD2 internalization to stabilize Nrf2. The release of prunetin inhibited the interaction of Kelch-like ECH-associated protein 1 with Nrf2 and promoted the nuclear translocation of Nrf2. In summary, this study unveiled that in skin inflammation, H@P@M activated and internalized DRD2, which subsequently formed a protein complex with arrestin beta 1-ubiquitin specific protease 8 (USP8)-Nrf2. Deubiquitination was performed to stabilize Nrf2 while promoting the nuclear translocation of Nrf2 to exert anti-inflammatory and antioxidant functions. STATEMENT OF SIGNIFICANCE: Skin is the body's largest physical barrier, always protecting the body from the interference of the external environment. However, excessive exposure to ultraviolet rays in the sun can cause skin inflammation, leading to skin erythema, itching, edema and pain, which can be troublesome in our daily lives. The complex mechanism of skin inflammation caused by ultraviolet radiation has not been fully clarified. In this study, the role of DRD2 in UV-induced skin inflammation was explored, and nano-composite particles HA@Prunetin@MPDA, which act on multiple targets in the anti-inflammatory pathway of DRD2, were developed to maximize the effect of the drug. It provides a new way to treat skin inflammation caused by UV.