Golgi-targeted copper delivery strategy via enhancing copper-dependent proteins' activity for fascia regeneration

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.