Direct Activation of Follicular Melanocytes by Polymeric Tyrosinase Nanocapsules for Reversing Hair Graying

Hair graying is a multifactorial pigmentary disorder resulting from melanocyte dysfunction. Effective treatment is challenging due to the deep localization of follicular melanocytes and the limited efficiency of current transdermal delivery systems for bioactive macromolecules. Here, we present a rationally designed transdermal therapy employing polymeric tyrosinase nanocapsules (nTYRs) for the direct activation of local melanocytes and in situ stimulation of melanogenesis. Guided by a penetration model established in our study, the size and surface potential of nTYRs were optimized to enhance skin permeability and preserve enzymatic activity. nTYRs efficiently delivered active tyrosinase through the stratum corneum to hair follicle melanocytes, resulting in rapid and robust hair repigmentation. Efficacy and safety were validated across mouse and human melanocyte models and porcine and human skin models. An immune-mediated endogenous hair graying mouse model was developed and employed to closely mimic human pathophysiology and directly assess the effects of nTYRs on damaged melanocytes. This study provides a promising and broadly applicable strategy for reversing hair graying with direct efficacy, minimal side effects, and strong potential for synergistic use with existing therapies.