A long-standing goal of nanomedicine is to improve a drug’s benefit by loading it into a nanocarrier that homes solely to a specific target cell and organ. Unfortunately, nanocarriers usually end up with only a small percentage of the injected dose (% ID) in the target organ, due largely to clearance by the liver and spleen. Further, cell-type-specific targeting is rarely achieved without reducing target organ accumulation. To solve these problems, we introduce DART (dual affinity to RBCs and target cells), in which nanocarriers are conjugated to two affinity ligands, one binding red blood cells and one binding a target cell (here, pulmonary endothelial cells). DART nanocarriers first bind red blood cells and then transfer to the target organ’s endothelial cells as the bound red blood cells squeeze through capillaries. We show that within minutes after intravascular injection in mice nearly 70% ID of DART nanocarriers accumulate in the target organ (lungs), more than doubling the % ID ceiling achieved by a multitude of prior technologies, finally achieving a majority % ID in a target organ. Humanized DART nanocarriers in ex vivo perfused human lungs recapitulate this phenomenon. Furthermore, DART enhances the selectivity of delivery to target endothelial cells over local phagocytes within the target organ by 6-fold. DART’s marked improvement in both organ- and cell-type targeting may thus be helpful in localizing drugs for a multitude of medical applications.

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Diseases of the pulmonary alveolus, such as pulmonary fibrosis, are leading causes of morbidity and mortality, but exceedingly few drugs are developed for them. A major reason for this gap is that after inhalation, drugs are quickly whisked away from alveoli due to their high perfusion. To solve this problem, the mechanisms by which nano‐scale drug carriers dramatically improve lung pharmacokinetics using an inhalable liposome formulation containing nintedanib, an antifibrotic for pulmonary fibrosis, are studied. Direct instillation of liposomes in murine lung increases nintedanib's total lung delivery over time by 8000‐fold and lung half life by tenfold, compared to oral nintedanib. Counterintuitively, it is shown that pulmonary surfactant neither lyses nor aggregates the liposomes. Instead, each lung compartment (alveolar fluid, alveolar leukocytes, and parenchyma) elutes liposomes over 24 h, likely serving as “drug depots.” After deposition in the surfactant layer, liposomes are transferred over 3–6 h to alveolar leukocytes (which take up a surprisingly minor 1–5% of total lung dose instilled) in a nonsaturable fashion. Further, all cell layers of the lung parenchyma take up liposomes. These and other mechanisms elucidated here should guide engineering of future inhaled nanomedicine for alveolar diseases.

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