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

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.