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.
Favaro et al. (Thu,) studied this question.