High-throughput screening-based design of multifunctional natural polyphenol nano-vesicles to accelerate diabetic wound healing

Oxidative stress is a major pathological factor that impedes the diabetic wound healing process. Procyanidins (PC) form nanoparticle-vesicles (PPNs) through hydrogen bonding and exhibit good drug delivery capability; however, its application in diabetic wound is not satisfied. To meet the antioxidant needs for treating, high-throughput screening in natural product library (NPL) under in vitro oxidative stress condition was conducted to enhance the antioxidant activity of PPNs. HUVECs treated with TBHP was established as screening model in vitro. Baicalein (BAI) was identified out of 600 + products in the library as the most effective one to combat oxidative stress. Further study showed that PC and BAI may react in equal proportions to synthesize new vesicles, named BPPNs; while BPPNs have ROS responsive and antioxidant effects. Network pharmacology showed that in diabetic wounds, the target genes of PC are mainly enriched in the VEGF-related pathways, while BAI primarily regulates tyrosine phosphorylation. The complementarity between the two has been validated in in vitro and in vivo experiments. In summary, the antioxidant drug BAI, identified through high-throughput screening of NPL, could optimize the biological function of PPNs; the newly-synthesized BPPNs may accelerate diabetic wound healing through dual mechanisms of promoting angiogenesis and combating oxidative stress.