Cupric-polymeric nanoreactors integrate into copper metabolism to promote chronic diabetic wounds healing

Given multifunction of copper (Cu) contributing to all stages of the physiology of wound healing, Cu -based compounds have great therapeutic potentials to accelerate the wound healing, but they must be limited to a very low concentration range to avoid detrimental accumulation. Additionally, the cellular mechanism of Cubased compounds participating the healing process remains elusive. In this study, copper oxide nanoparticles (CuONPs) were synthesized to mimic the multiple natural enzymes and trapped into PEG-b-PCL polymersomes (PS) to construct cupric -polymeric nanoreactors (CuO@PS) via a direct hydration method, thus allowing to compartmentalize Cu -based catalytic reactions in an isolated space to improve the efficiency, selectivity, recyclability as well as biocompatibility. While nanoreactors trafficked to lysosomes following endocytosis, the released Cu -based compounds in lysosomal lumen drove a cytosolic Cu+ influx to mobilize Cu metabolism mostly via Atox1-ATP7a/b-Lox axis, thereby activating the phosphorylation of mitogen-activated protein kinase 1 and 2 (MEK1/2) to initiate downstream signaling events associated with cell proliferation, migration and angiogenesis. Moreover, to facilitate to lay on wounds, cupric -polymeric nanoreactors were finely dispersed into a thermosensitive Pluronic F127 hydrogel to form a composite hydrogel sheet that promoted the healing of chronic wounds in diabetic rat models. Hence, cupric -polymeric nanoreactors represented an attractive translational strategy to harness cellular Cu metabolism for chronic wounds healing.