Multimodal imaging and deep learning unveil pulmonary delivery profiles and acinar migration of tissue-resident macrophages in the lung

Abstract Holistic deciphering of spatially-resolved delivery and biokinetics of nanoparticles (NPs) in the lung, along with the mobility of tissue-resident macrophages (TRMs) and their role in regulating NP cellular fate, remains unclear. Multimodal imaging and deep learning were applied to elucidate the longitudinal inter- and intra-acinar deposition features and regional dosimetry of NPs. The initial NP distribution patterns depended significantly on the pulmonary delivery routes and were most uniform for aerosol inhalation. Artificial intelligence-driven 3D airway segmentation enabled direct determination of bronchial and acinar NP dose. Longitudinal imaging uncovered an intra-acinar NP kinetics profile independent of delivery route. Contrary to the traditional notion of passive diffusion, this study reveals that long-term NP lung retention is facilitated by intra-acinar NP transport mediated by phagocytosis and patrolling of TRMs. Overall, this study elucidates the complexities of NP-lung delivery features and TRM immunity on the fate of biopersistent NPs.