DLD‐HLNP/P@IR780 for efficient lung‐parenchyma accumulation to treat idiopathic pulmonary fibrosis

Abstract Efficient lung targeting is the criterion for nanomedicines to treat pulmonary diseases. The low delivery of payloads to lung parenchyma is due to the elimination of reticuloendothelial system and the inhibition of pulmonary endothelial cell barriers. In this study, we discovered the efficient lung‐targeting capability of dendritic–linear–dendritic polymer hybridized LNP@780 (DLD‐HLNP@IR780) nanoparticles to achieve high lung/liver ratios ranging from 20 to 30. The exploration of targeting mechanism revealed that the IR780 iodide possessed high affinity to CD300LF and MRC1, which was specifically expressed on pulmonary endothelial cells (ECs) and macrophages. The CD300LF mediated the DLD‐HLNP@IR780 nanoparticles to traverse ECs ， and macrophages helped nanoparticles aggregate in lung parenchyma via MRC1. The DLD‐HLNP@IR780 nanoparticles loaded with pirfenidone (DLD‐HLNP/P@IR780) were adopted to achieve lung‐parenchyma‐targeted release of pirfenidone to treat idiopathic pulmonary fibrosis (IPF) and exhibited efficiently attenuated IPF progression. It provided an easy and potent strategy for fabricating lung‐targeting nanomedicines to treat multiple pulmonary diseases.