In Vivo Chemotaxis System with Ultra-High Ionic Tolerance

Abstract The construction of artificial chemotactic systems capable of efficient operation in vivo is crucial for achieving precise drug delivery. However, current systems are generally limited by insufficient substrate concentrations in lesion regions and the suppression of chemotactic driving forces imposed by high ionic strength in physiological environments. To address these challenges, this study develops a chemotactic system based on inducible nitric oxide synthase‑arginine (iNOS‑Arg), which exhibits outstanding chemotactic performance and ultrahigh ion tolerance (~135 mM) in both in vitro and in vivo tumor models. Using particle‑based mesoscale simulations (hybrid molecular dynamics-multiparticle collision dynamics), we reveal for the first time the thermally enhanced self‑electrophoresis driving mechanism of this system and elucidated the principle underlying its directional motion in environments with trace iNOS gradients and high ionic strength. Theoretical simulations and experimental results consistently demonstrate that the locomotion of this chemotactic system does not rely on structural asymmetry. The kinetic model established in this study integrates multiple physicochemical processes, including catalytic reactions, hydrodynamic behaviors, heat conduction, mass transport, thermal fluctuation, making it more representative of the complex in vivo microenvironment. This model not only provides a theoretical framework for understanding biomimetic chemotactic behaviors but also opens new avenues for the design of high‑efficiency targeted delivery systems adapted to real physiological environments.