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Noha Khalifa Abo Aasy,1 Sarah A El-Lakany,1 Perusi M Masanga,2 Elbadawy A Kamoun,3,4 Shahira H EL-Moslamy,5 Marwa Abu-Serie,6 Rania G Aly,7 Nazik A Elgindy1 1Department of Industrial Pharmacy, Faculty of Pharmacy, Alexandria University, Alexandria, Egypt; 2St John’s University of Tanzania, Dodoma, Tanzania; 3Polymeric Materials Research Department, Advanced Technology and New Materials Research Institute (ATNMRI), City of Scientific Research and Technological Applications (SRTA-City), New Borg El-Arab City, Egypt; 4Nanotechnology Research Center (NTRC), The British University in Egypt (BUE), El-Sherouk City, Cairo, 11837, Egypt; 5Bioprocess Development Department (BID), Genetic Engineering and Biotechnology Research Institute (GEBRI), City of Scientific Research and Technological Applications (SRTA-City), New Borg El-Arab City, Alexandria, 21934, Egypt; 6Medical Biotechnology Department (MBD), Genetic Engineering and Biotechnology Research Institute (GEBRI), City of Scientific Research and Technological Applications (SRTA-city), New Borg El-Arab City, Alexandria, 21934, Egypt; 7Department of Surgical Pathology, Faculty of Medicine, Alexandria University, Alexandria, EgyptCorrespondence: Sarah A El-Lakany, Department of Industrial Pharmacy Faculty of Pharmacy, Alexandria University, 1 El Khartoum Square, PO Box 21521, Alexandria, Egypt, Tel +201002828663, Fax +203 4871668, Email sarah.ellakany@alexu.edu.eg; sarah.abdalla89@gmail.comPurpose: Diabetes mellitus is among the disrupting factors of orchestrated events in wound healing. This necessitates the urge for tailored medications, which are continually offered by nano-sized materials. Herein, we present greenly synthesized copper oxide nanoparticles (CuO NPs), obtained from either Punica granatum L. (PG) or Pisidium guajava L. (GV) extract, to function as potent bactericidal and fungicidal materials that promote regeneration and healing of the targeted diabetic wounded tissues.Methods: PG or GV plant extracts were compared as source of reducing agents for CuO NPs synthesis process. The yield and photocatalytic degradation potential were compared. NPs obtained from the superior extract, PG, were characterized using particles size, zeta potential, XRD, TEM, SEM, and EDX. The antimicrobial effects were evaluated on multidrug-resistant human pathogens and then the percentage biofilm inhibitory concentration was determined. The cytotoxicity and wound scratch study were conducted on a normal human skin cell line. In-vivo wound healing activity in diabetic rats was assessed along with histopathological and immunohistochemical examination of CD45 and α-SMA.Results: The greenly synthesized CuO NPs are spherical in shape having a diameter of 233nm. CuO NPs (250μg/mL) acted as promising biocontrol agent against a variety of multidrug-resistant human pathogens. They significantly exhibited 29.460± 0.811% healing of the scratched wound compared to only 2.001± 0.155% for the control. Wound healing experiments revealed the safety of a low CuO NPs concentration in a diabetic animal model as well as on human normal skin fibroblast cell line. The treated group with a dose of 2mg/cm2 showed superior results with a WC50 value of 7.2 days, and 92% wound contraction after 13-days. Immunohistochemical investigation of the same group demonstrated well-established fibrous tissue (5.7± 3.7/HPF), and an amplified granulation tissue of recently developed blood vessels (70± 1.5/HPF).Conclusion: Green synthesized CuO NPs could overcome drug resistance and promote wound healing process effectively.Keywords: plant extraction, metal ion, cell compatibility, wound contraction, biofilm inhibitory concentration