Multimodal 4D imaging and deep learning unveil acinar migration of tissue-resident, nanoparticle-laden macrophages in the lung

Abstract

Pulmonary delivery of therapeutic drugs or toxic substances has been widely applied to treat human lung diseases or understand environmental-induced lung injury, respectively. However, systemic biodistribution and biokinetics of delivered substances or nanoparticles(NPs) and the role of the innate immune system remain unclear. We applied multimodal imaging combined with artificial intelligence by deep learning-based whole-lung segmentation pipelines(convolutional neural network) to reveal the distinct diversities in NP deposition and biokinetics for common delivery routes and particularly the role of tissue-resident macrophages (TRM) in mediating acinar NP mobility.

Novel delivery features and substantial deposition variations for 6 liquid-based delivery routes were first revealed by 4D imaging and AI at whole-lung cellular-resolution level, e.g., aerosol deliveries result in evener inter-acinar distribution modes with central/peripheral deposition closing to unity and higher acinar/airway deposition ratios, and ventilator-assisted aerosol delivery causes a hotspot aerosol accumulation in proximal area of intra-acini(>10-fold). Proximal acinar deposited NPs were removed from the epithelium and found in TRM, leading to a relatively even alveolar NP distribution. Intravital microscopy, ex vivo 4D live tissue microscopy, in situ 3D optical microscopy, ex vivo NPs-lung interaction model, and flow cytometry proved TRM (Cd11b⁺, and SiglecF⁺) relocate the NPs via phagocytosis and migration through the epithelial surface or pores of Kohn. This study offers novel lung delivery features and convincing mechanisms of TRM mobility in executing innate immune function.