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 Cu-based 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.