Zn‐Based Multi‐Active Framework Nanoparticles TSA‐CAN‐Zn Inhibit Skin Glycation via Dual Blockade of HMGB1/RAGE and AGEs/RAGE Pathways

Abstract Receptor for advanced glycation end products (RAGE) plays an important role in skin glycation damage. High‐mobility group 1B protein (HMGB1) and advanced glycation end products (AGEs) are key RAGE ligands. Simultaneous inhibition of HMGB1/RAGE and AGEs/RAGE pathways maybe an effective strategy to alleviate glycation induced skin damage. In this work, Theasinensin A (TSA) is identified as the active molecule inhibiting HMGB1‐RAGE interaction through molecular docking. To simultaneously suppress HMGB1/RAGE and AGEs/RAGE pathways, Zn‐based multi‐active framework nanoparticles TSA‐CAN‐Zn are designed, which contain TSA and the active molecule L‐carnosine (CAN) that inhibits AGEs production. In vitro studies demonstrated that TSA‐CAN‐Zn have radical scavenging activity and AGEs formation inhibition activity. TSA‐CAN‐Zn can not only inhibit ROS accumulation, cell apoptosis, and inflammatory factors production induced by glycation in HaCaT cells but also enhanced the lysosomal degradation of AGEs. TSA‐CAN‐Zn also mitigated the damage caused by glycation in mouse skin glycation model. Single‐cell RNA sequencing results revealed the impact of TSA‐CAN‐Zn on different cell types of skin tissue, especially the basal cells of the epidermal layer and inflammation‐related macrophages. And pathway analysis revealed that TSA‐CAN‐Zn mainly influences the downstream pathways of RAGE. Collectively, TSA‐CAN‐Zn is a promising therapeutic candidate for ameliorating glycation‐induced skin damage.