Iridium Nanoparticle-GatedJanus Nanomachines forEnzyme-Controlled Drug Delivery

Abstract Controlled drug delivery systems (DDSs) have emerged as a promising alternative to conventional therapies, aiming to optimize drug release profiles and improve therapeutic outcomes while reducing systemic side effects. In this work, iridium-gated Janus nanomachines are proposed as enzyme-regulated platforms for smart and autonomous drug delivery. These hybrid nanostructures consist of mesoporous silica nanoparticles asymmetrically functionalized with gold nanoparticles bearing surface-anchored enzymes on the metallic hemisphere, while the opposite mesoporous face incorporates pH-responsive molecular gates based on aminophenylboronic acid and d-lactose-functionalized iridium nanoparticles, enabling efficient cargo loading and motility behavior. To evaluate nanomachine operation, two enzymatic systems were employed: glucose oxidase (GOx) and a tandem esterase/alcohol oxidase (AOX) system, using spectrophotometric monitoring of the model cargo release. Both platforms exhibited well-defined release kinetics and good correlation between substrate concentration and high selectivity toward their respective inputs. Motility studies revealed the appearance of two particle populations in the presence of glucose or methanol, consistent with enhanced motion driven by catalytic reactions at the iridium nanoparticle surface upon enzymatic hydrogen peroxide generation. Finally, the GOx-based nanomachine loaded with the antitumoral drug doxorubicin (DOXO) demonstrated efficient cellular internalization, preserved biocompatibility, and enhanced antitumoral activity in HeLa cells. Overall, this work reinforces the potential of enzyme-controlled Janus nanomachines as multifunctional platforms integrating autonomous motion and stimulus-responsive drug delivery for advanced therapeutic applications.