Diverse Amino Acid Capping of Monodispersed Iron Oxide Nanoparticles via Reverse-Microemulsion-Based Ligand Exchange: A Versatile Platform for Bioapplication

Amino acid-functionalized iron oxide nanoparticles (IONPs) have emerged as versatile platforms for biomedical applications, including targeted drug delivery, magnetic resonance imaging contrast enhancement, magnetic hyperthermia, and biosensing. These systems exploit the molecular recognition capabilities of amino acid residues toward biological targets. However, conventional coprecipitation methods, which typically produce hydrophilic IONPs smaller than 10 nm, often exhibit surface heterogeneity, uncontrolled multilayer adsorption, and limited compatibility with diverse amino acid chemistries. Here, we report a generalizable and robust reverse microemulsion approach that enables the direct functionalization of hydrophobic IONPs with amino acids. The resulting nanoparticles are monodispersed, uniformly spherical, and tunable in size from 5 to 20 nm. This strategy enables covalent or coordinative attachment of a wide range of amino acids─positively charged (arginine, histidine, and lysine), negatively charged (aspartic acid and glutamic acid), hydrophobic (tyrosine), and sulfur-containing (cysteine), demonstrating the coating versatility and chemical tunability of the platform. We further examined the biomedical performance of three charged amino acid-coated IONP systems with polar side chains for protein and anticancer drug delivery. This facile and modular approach provides a route to engineer amino acid-functionalized magnetic nanostructures with controlled surface chemistry and broad potential in theranostic and biointerfacing applications.