Cupric-polymeric nanoreactors integrate into copper metabolism to promote chronic diabetic wounds healing
Open accessAbstract
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 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.
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Copper-treated wounds show significant increase in VEGF and number of blood vessels compared to controls.
“One of the notorious effects noticed in some of these studies was the significant increase in VEGF and the number of blood vessels in the copper-treated wounds as compared to the controls [72,73,75,77,78,84,97,103].”
From The Journey of Copper-Impregnated Dressings in Wound Healing: From a Medical Hypothesis to Clinical Practice (2025) · cites this paper as [77]
The Results section on diabetic rats reports that newly formed blood vessels increased in CuOPSφGEL-treated wounds compared with other groups. The in vitro Results report increased VEGFA in copper-treated cells, but the paper does not report increased VEGF in the treated wounds themselves. Page numbers are unavailable in our copy. (LLM, conf=0.88)
Experimental — accuracy not yet measuredCopper-containing biomaterials consistently demonstrate enhanced healing of non-infected wounds in animal models compared to controls.
“These studies consistently demonstrate enhanced healing of non-infected wounds [71,72,73,74,75,76], including those in diabetic [77,78,79,80,81,82,83] and burn-related [84,85,86,87,88,89,90] animal models when compared to control materials.”
From The Journey of Copper-Impregnated Dressings in Wound Healing: From a Medical Hypothesis to Clinical Practice (2025) · cites this paper as [77]
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- Authors
- Tang, Q., Tan, Y., Leng, S., Liu, Q., Zhu, L., & Wang, C.
- Affiliations
- Sun Yat-sen University (CN)
- Wuhan Union Hospital (CN)
- The Seventh Affiliated Hospital of Sun Yat-sen University (CN)
- Guangdong Medical College (CN)
- Corresponding author
- Zhu, Linyu
- Wang, Cuifeng
- Venue
- Materials Today Bio
- Publisher
- Elsevier BV
- Published
- 2024-06
- Volume
- 26
- Pages
- 101087
- ISSN
- 2590-0064 (ISSN-L)
- PMC
- PMC11111831
- OpenAlex
- W4396835037
- Cited by
- 11
- References
- 71
- Citations by year
- 2026: 2 · 2025: 7 · 2024: 2
- FWCI
- 1.75
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Materials Today Bio (publishedVersion, cc-by-nc)
- PubMed Central (publishedVersion, cc-by-nc)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Guangdong Medical Research Foundation (A2021196, 20221800905702)
- Science and Technology Planning Project of Guangdong Province (2021A0505030025)
- National Natural Science Foundation of China (82073772)
- Guangzhou Municipal Science and Technology Project (202102080266)
- Natural Science Foundation of Jiangxi Province (20212ACB206030)
- Basic and Applied Basic Research Foundation of Guangdong Province (2021B1515140044, 2023A1515010613, 2019A1515010632)
- Topics
- Health Sciences › Medicine › Rehabilitation › Wound Healing and Treatments
- Physical Sciences › Materials Science › Biomaterials › Electrospun Nanofibers in Biomedical Applications
- Health Sciences › Medicine › Surgery › Tissue Engineering and Regenerative Medicine
- Keywords
- copper oxide nanoparticles, polymersomes, PEG-b-PCL, copper metabolism, MEK1/2 phosphorylation, diabetic wound healing, chronic wounds, angiogenesis, cell proliferation and migration, thermosensitive hydrogel
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