Golgi-targeted copper delivery strategy via enhancing copper-dependent proteins' activity for fascia regeneration.
This study introduced a Golgi-targeted copper delivery system (LNP-ATOX1/GHK-Cu@PCL-GelMA) designed to enhance the activity of copper-dependent proteins—particularly lysyl oxidase (LOX)—to promote fascia regeneration. The system combined GHK-Cu (a copper-peptide complex) as a sustained-release copper source with lipid nanoparticles (LNPs) delivering mRNA encoding ATOX1, a copper chaperone that shuttles copper into the Golgi apparatus via ATP7A/B transporters. In vitro experiments showed the system significantly increased Golgi copper accumulation, raised LOX activity to approximately 1.78 times that of controls, and enhanced angiogenic capacity. The researchers also reported that ATOX1 upregulation promoted copper-dependent translocation of ATP7A and Rac1 to the plasma membrane, potentially supporting neovascularization. In a rabbit fascia defect animal model, the strategy improved collagen alignment, neovascularization, and extracellular matrix reconstruction. Limitations include the absence of human or large-animal data, reliance on a single animal model, and the translational gap between rabbit fascia repair and human clinical outcomes. No human trials were conducted.
Why this grade: All in vivo data were derived exclusively from a rabbit fascia defect model with supporting in vitro experiments; no human subjects were studied.
Copper-dependent proteins (such as lysyl oxidase, LOX) require copper acquisition within the Golgi apparatus to achieve enzymatic activation, and insufficient activation of these proteins is a key factor limiting fascia regeneration. To address this issue, this study, for the first time, proposes and validates a Golgi-targeted copper delivery system (LNP-ATOX1/GHK-Cu@PCL-GelMA). In this system, GHK-Cu serves as a stable copper source to provide a sustained release of Cu ions for cellular uptake, while lipid nanoparticles (LNPs) are used to deliver mRNA encoding the copper chaperone ATOX1. Upregulation of ATOX1 facilitates the transport of copper into the Golgi apparatus via ATP7A/B, thereby enhancing the activity of copper-dependent proteins. In addition, ATOX1 promotes the copper-dependent translocation of ATP7A and Rac1 to the plasma membrane, synergistically accelerating neovascularization. In vitro studies demonstrated that this material system significantly increased copper accumulation within the Golgi apparatus, elevated LOX activity to 1.78 times that of the control group, and enhanced angiogenic capacity. In a rabbit fascia defect model, this strategy effectively promoted collagen alignment and neovascularization, improving extracellular matrix reconstruction and facilitating fascia regeneration. In conclusion, this work establishes a novel Golgi-targeted copper delivery strategy, providing a practical therapeutic approach for regenerative disorders caused by insufficient activation of copper-dependent proteins, such as fascia defects.
Educational summary of published research — not medical advice. Full text is shown only where licensing permits.