Pulmonary surfactant ferries drugs in a breathing lung-on-chip

Deep in our lungs a thin film called pulmonary surfactant keeps air sacs open and protects the delicate air–liquid interface. That same surfactant is thought to act as a final carrier — a “last mile” — for inhaled particles and medicines, but studying this vehiculation has been difficult. Animal models and standard liquid cell cultures do not reproduce the thin, breathing surface of the alveolus, so important questions about how drugs travel and where they end up have remained unanswered. To tackle this, a team led by Vivek V. Thacker adapted a thin-film bridge (TFB) delivery method, previously used in acellular studies, to a lung-on-chip (LoC) platform that mimics breathing-like stretch at the alveolar interface. By bringing the thin surfactant film and a mechanically active chip together, the researchers were able to recreate the conditions where surfactant might pick up and carry lipophilic therapeutics to cells in the distal lung. This setup allowed direct observation of how drugs behave at the real air–liquid boundary rather than in bulk liquid.

The investigators used confocal live-imaging to watch fluorescently-labelled cargoes move with the surfactant film and enter cells. They tested lipophilic compounds including Tacrolimus and Beclomethasone and compared TFB vehiculation to existing in vitro delivery approaches. The TFB method, applied to human LoCs under breathing-like stretch, promoted sustained retention of functionally effective Tacrolimus and strong co-localization of the drug with surfactant lipids. When human LoCs were reconstituted with in vitro–differentiated alveolar macrophage-like cells, the TFB-vehiculated drugs accumulated in those macrophages rather than being taken up predominantly by alveolar epithelial cells, which was the pattern seen with unphysiological liquid formulations. In a proof-of-concept antimicrobial test, bedaquiline delivered via TFB vehiculation suppressed subsequent growth of Mycobacterium tuberculosis in a prophylactic experiment, demonstrating that surfactant-mediated delivery can carry antibiotics in a way that affects bacterial outcomes in the model.

Together these experiments show a practical way to study and exploit the carrier role of surfactant at the alveolar interface. By recreating a thin-film, breathing surface and using the thin-film bridge approach on a lung-on-chip, the team demonstrated that lipophilic therapeutics and antibiotics can hitch a ride on surfactant, be retained at the air–liquid boundary, and be delivered selectively to cells such as alveolar macrophage-like cells. This contrasts with traditional liquid-based delivery that favors epithelial uptake and may misrepresent how inhaled drugs behave in the real lung. The work establishes that surfactant-containing therapeutic formulations are feasible for direct pulmonary delivery in vitro and provides a platform for testing how formulation and mechanics influence where drugs go and how long they remain. Although further work will be needed to translate these findings beyond the chip, the study opens a route toward inhaled therapies designed to use the lung’s own surfactant as a last-mile delivery vehicle.