Natural exosome-like nanoparticles derived from ancient medicinal insect Periplaneta americana L. as a novel diabetic wound healing accelerator

Along with the recognized therapeutic outcomes of regenerative medicine, extracellular vesicles and their exosome subsets have become an alternative option for wound healing. Periplaneta americana L. (PA), an ancient and traditional medicinal insect, has been around for 300 million years, and displays magic formidable vitality and environmental adaptive ability. The linkage between intrinsic amputation regeneration feature and the acknowledged wound healing medicinal benefit of PA has never been revealed. Herein, inspired by the ability of exosomes to participate in the interkingdom communication, we explored whether this effect was ascribed to PA derived exosome-like nanoparticles (PA-ELNs). PA-ELNs were extracted by differential velocity centrifugation approach and characterized by DLS, NTA and TEM. Their cargoes were analyzed by LC-MS/MS proteomics and small RNA-seq analysis. The wound healing activity was verified in vivo and in vitro. PA-ELNs with a concentration of 2.33x10⁹±6.35x10⁷ particles/mL exhibited a lipid bilayer-bound membrane structure with an average size of 104.7 nm. Furthermore, the miRNA cargoes in PA-ELNs participate in some wound healing related signal pathways such as TGF-beta, mTOR, and autophagy. As expected, the in vitro tests indicated that PA-ELNs were apt to be internalized in HUVECs, L929 and RAW 264.7 cells and contributed to cell proliferation and migration. Most importantly, we demonstrated that the topical administration of PA-ELNs could remarkably accelerate wound healing in a diabetic mouse model, and was involved in anti-inflammatory, re-epithelialization and autophagy regulation. This study provides clear evidence for the first time that PA-ELNs, as diabetic wound healing accelerators, are the "bioactive code" of this ancient medicinal insect.