Abstract

Micro/nanorobots offer a promising approach for active therapeutic delivery to hard-to-access regions of the body. For pulmonary fibrosis, however, targeted drug delivery remains difficult because the disease has spatially heterogeneous fibrotic lesions and mucus accumulation. Importantly, achieving lesion targeting and mucus penetration remains challenging due to the trade-off between long-distance navigation and the ability to traverse dense biological barriers. Here, we present a hierarchically structured microrobot that integrates magnetically driven microrollers with self-propelled enzymatic nanomotors for sequential drug delivery via a thioketal linker responsive to reactive oxygen species (ROS). The hierarchical microrobots exhibit programmable navigation on inclined, mucus-coated surfaces under airflow and undergo disassembly in oxidative fibrotic environments. Following deployment, the released enzymatic nanomotors actively penetrate mucus barriers and deliver anti-fibrotic drugs. In a three-dimensional (3D) in vitro fibrosis model incorporating a mucus-epithelial barrier, drug-loaded enzymatic nanomotors achieve superior penetration and significantly greater anti-fibrotic efficacy than passive nanoparticles. Overall, this work establishes a hierarchical microrobotic platform that enables both targeted transport and active mucus penetration for localized therapeutic delivery in complex biological environments and provides a general strategy for integrating targeting and tissue penetration within a single platform.