Smart Nanogels as Enzyme‐Driven Nanomotors for Navigating Viscous Physiological Barriers

Abstract In recent years, enzyme‐powered nanomotors (NMs) have emerged as promising tools for biomedical applications. They exhibit active motion in complex media, whereas traditional passive nanoparticles (NPs) typically remain trapped. Despite their potential, nanogels (NGs)—3D, cross‐linked polymeric networks with high water retention and environmental responsiveness—remain underexplored as cores for enzymatic NMs. Here, fine‐tuned NGs designed to confer smart properties are presented, allowing them to adapt their size and density in response to external stimuli (e.g., pH, temperature, and redox conditions). After anchoring urease to these NGs to produce nanogel‐nanomotors (NGs‐NMs), they exhibited both individual and collective motion at a very low urea concentration, enabling displacement in highly viscous environments. To achieve this, four NGs formulations based on p‐(N‐isopropylacrylamide) co‐polymerized with p‐Itaconic acid (p‐(NIPAM‐co‐IAc)) are developed, cross‐linked with either N,N′‐methylenebisacrylamide (BIS) and/or N,N′‐bis(acryloyl)cystamine (BAC), and coated with p‐(2‐hydroxyethyl methacrylate) (p‐HEMA). This results, obtained via confocal microscopy and flow cytometry, demonstrate their rapid cell internalization. Moreover, synchrotron‐based infrared spectroscopy (SR‐FTIRM) allowed to demonstrate that NGs‐NMs can tune the physicochemical composition of tumoral cells. This findings underscore the potential of NGs‐NMs, combining adaptability, safety, and efficacy. They represent the evolution in NMs technology, paving the way for groundbreaking advancements in personalized medicine.