Hydrogen Bond Mediated Phase Separation of Phenolic-Based Compounds for the Preparation of Melanin-like Nanoparticles

Melanin-like nanoparticles (MLNPs) hold great promise for biomedical applications, yet their controlled synthesis under mild conditions remains challenging. Here, we present a hydrogen bond-mediated liquid–liquid phase separation (LLPS) strategy to fabricate functional MLNPs with tunable physicochemical properties. Coacervates are formed through hydrogen bonding between hydrogen bond donor polyphenols and hydrogen bond acceptor polymers, providing a dynamic and mild environment for nanostructure formation. Leveraging this hydrogen bond-stabilized coacervate as a soft template, we synthesized monodisperse MLNPs via oxidative polymerization of coacervates. The resulting nanoparticles feature precise size control and abundant surface functionalities, enabling drug loading via electrostatic interactions, hydrogen bonding, π-π stacking, and metal-ion coordination. These multifunctional properties support diverse biomedical applications, including drug delivery, imaging, and enzyme-mimetic catalytic therapy. This work establishes a scalable and versatile platform for engineering MLNPs via hydrogen bond-driven LLPS templating, opening up opportunities for translational nanomedicine.