Bio‐Responsive <scp>Hyaluronic Acid‐Stearylamine</scp> Copolymer as an Enzyme Responsive Drug Carrier System: Intelligent Fusidic Acid Loaded Nanomicelles for Potential Treatment of Bacterial Wound Infections

ABSTRACT Amphiphilic copolymer‐based nanocarriers have revolutionized drug delivery platforms by offering versatile encapsulation of both hydrophilic and hydrophobic drugs and site‐specific drug delivery. This study presents a bio‐responsive copolymer synthesized by a modified amidation reaction of hyaluronic acid and stearylamine. The bio‐responsive HA‐g‐SA copolymer characterized through 1 H‐NMR and ATR‐FTIR spectroscopy revealed distinct spectral shifts indicative of the formation of an amide bond. XRD and DSC analysis validated the integration of both subunits, highlighting the semi‐crystalline nature and thermal behavior consistent with successful synthesis. HA‐g‐SA copolymers demonstrated enzymatic degradation by Hyaluronidase, an enzyme secreted by Staphylococcus aureus , which degrades the copolymer, facilitating precise, site‐specific, on‐demand drug release. Fusidic acid nanomicelles (FA‐NMs) were developed and characterized by SEM, particle size, zeta potential, polydispersity index, entrapment efficiency, loading capacity, in vitro drug release, cytotoxicity, and enzyme‐triggered degradation. FA‐NMs exhibited an optimal PS of 181 nm, ZP of −14.4 mV, and exceptionally low PDI of 0.18, reflecting outstanding colloidal stability and uniformity with a high encapsulation efficiency of 87% and loading capacity of 186.5 mg/g. FA‐NMs exhibited a sustained, enzymatic release profile, with enzyme‐triggered degradation substantiating the responsiveness to bacterial enzymes. This adaptive, bio‐response strategy underscores sustained site‐specific release, reducing off‐target impact and enhancing treatment efficacy.