Reconstructing protein conformations to activate follicular enzyme-nutrient reservoirs for reversing follicle aging

Hair regeneration depends on a reservoir of follicular enzymes that regulate the microenvironment and provide metabolic support. However, in degenerative alopecia, this enzymatic reservoir is disrupted, impairing microenvironmental homeostasis. Here, through bioinformatics and molecular dynamics analyses, we revealed that several Zn 2+ /Cu 2+ -dependent proteases ( e.g. , LOX and SOD1) were downregulated and exhibit aberrant conformations and activities in degenerative alopecia, further weakening microenvironmental support. To address this, we developed a Zn 2+ /Cu 2+ -doped decellularized extracellular matrix microneedle patch (dECMMA Zn/Cu ) to rapidly restore the follicular microenvironment and enzymatic reservoir function. In vitro , microneedle delivery of dECMMA Zn/Cu significantly upregulated key Zn 2+ /Cu 2+ -dependent proteases. Restoration of the enzymatic reservoir reduced p16 expression in dermal papilla stem cells, inhibited cellular senescence, and promoted stem cell proliferation. In a classical degenerative alopecia animal model, dECMMA Zn/Cu microneedle treatment resulted in denser and more continuous dermal collagen, a significant increase in hair follicle numbers, and promoted hair regeneration. In summary, this study establishes an innovative microneedle material that restores follicular function by remodeling protein conformation and activating the enzymatic reservoir. Currently, no studies have focused on the effect of the follicular enzymatic reservoir on hair regeneration. In degenerative alopecia, Zn 2+ /Cu 2+ -dependent proteases such as LOX and SOD1 are downregulated and structurally destabilized. We developed a Zn 2+ /Cu 2+ -doped decellularized matrix microneedle patch (dECMMA Zn/Cu ) to restore enzymatic activity and follicular function. This system reactivated key proteases, reduced P16 expression, suppressed senescence, and promoted hair regeneration. Overall, the dECMMA Zn/Cu microneedle rejuvenates the follicular niche by remodeling protein conformation and reestablishing the enzymatic reservoir. • In hair follicle aging disorders, bioinformatics analysis revealed that multiple metal ion-dependent proteins exhibit conformational instability and loss of enzymatic activity, thereby accelerating the aging process of hair follicles. • The developed zinc/copper dual-ion hybrid decellularized extracellular matrix microneedle system (dECMMA Zn/Cu ) targets the dermis, where ion matrix synergism reconstructs protein conformation and restores metalloprotein activity, rebuilds the follicular microenvironment and promots hair regeneration.