Sprayed copper peroxide nanodots for accelerating wound healing in a multidrug-resistant bacteria infected diabetic ulcer

Abstract

Vascular dysfunction and bacterial infection are key factors for the non-healing of diabetic ulcers. Growth factors and antibiotics seem to effectively target both issues. However, the short half-life and high cost of growth factors and the antibiotics resistance of bacteria greatly limit their further widespread applications. Novel strategies or agents with both angiogenic and antibacterial activities are urgently desirable. Copper peroxide (CuO₂) nanodots were reported to be decomposed into Cu²⁺ and H₂O₂ under mild acid conditions (pH 5.5). Considering that both decomposed products are acknowledged antibacterial agents (Cu²⁺, H₂O₂) and angiogenesis activator (Cu²⁺), we believe that CuO₂ nanodots are suitable for diabetic ulcer treatment because the pathological environment of infected chronic wounds is mildly acidic with pH 5.5-5.6. As expected, <i>in vitro</i> experiments showed that CuO₂ nanodots possessed excellent bactericidal properties against <i>Escherichia coli</i>, <i>Staphylococcus aureus</i>, <i>Pseudomonas aeruginosa</i>, and even methicillin-resistant <i>Staphylococcus aureus</i> (MRSA). CuO₂ nanodots induced the high expression of hypoxia-inducible factor (HIF-1α) and vascular endothelial growth factor (VEGF) in human umbilical vein endothelial cells (HUVECs), subsequently promoting the cell migration and tube formation for angiogenesis. In particular, CuO₂ nanodots exhibited good dispersibility and sprayable behavior in water. <i>In vivo</i> experiments demonstrated that the spayed CuO₂ nanodots in the wound area could effectively combat MRSA, reduce inflammation, promote angiogenesis, and consequently accelerate wound healing. Moreover, the sprayed CuO₂ nanodots in the wound sites caused negligible system toxicity. This study provides proof-of-principle evidence for applying the sprayed CuO₂ nanodots for infected diabetic ulcer treatment.