ACS Mater Lett

The effective dermal delivery of functional proteins could substantially improve therapeutic options for common skin disorders, in which current lipid-based or invasive strategies face efficacy and safety limitations. We report a biomimetic protein depot platform based on granular, nontoxic amyloids generated through Zn-mediated coordination of hexahistidine-tagged proteins. Functionalization of these materials with either the cell-penetrating peptide R9 or the tight junction modulator c-CPE, the C-terminal region of the Clostridium perfringens enterotoxin, enabled a systematic evaluation of transdermal penetration in mouse models. Whereas plain and R9-functionalized granules showed restricted permeation, c-CPE-functionalized granules achieved consistent distribution through the dermis into the hypodermal layers. These findings establish self-assembled protein amyloids as a promising and adaptable class of biomaterials for dermal protein delivery. Also, the ability of c-CPE to enhance permeability without auxiliary adjuvants, lipids, or invasive methods highlights the translational potential of this system for clinically applicable, noninvasive management of cutaneous conditions.