Biomimetic engineered polymer nanogels for targeted tyrosinase inhibition and transdermal delivery

Abstract

Tyrosinase is the key rate-limiting enzyme in melanogenesis and a central therapeutic target for hyperpigmentation disorders. Here, we report biomimetic polymer nanogels, termed tyrosinase-inhibitory nanogels (TINGs, 20–25 nm) designed to achieve potent tyrosinase inhibition and efficient transdermal delivery. By integrating phenolic and imidazole motifs within a hydrophilic polymer network, the TINGs mimic natural tyrosine substrates and coordinate with the enzyme's binuclear copper active site, leading to strong competitive inhibition. The nanoscale size and hydrogel matrix enable efficient skin penetration and intracellular delivery, circumventing the limitations of conventional small-molecule inhibitors. Mechanistic studies demonstrate that inhibition arises from synergistic substrate-mimetic recognition, copper chelation, hydrophobic stabilization, and nanoscale confinement. TINGs exhibit ultralow IC₅₀ values (∼22 × 10⁻⁷ mol·L⁻¹) and robust suppression of tyrosinase activity and melanin production in both cellular and murine models. This work establishes a generalizable platform for designing abiotic, polymer-based enzyme inhibitors with intrinsic functionality and transdermal delivery capability, providing a new strategy for precise modulation of skin pigmentation.