Pulmonary delivery of nanomedicines is very promising in lung local disease treatments whereas several physiological barriers limit its application via the interaction with inhaled nanomedicines, namely bio-nano interactions. These bio-nano interactions may affect the pulmonary fate of nanomedicines and impede the distribution of nanomedicines in its targeted region, and subsequently undermine the therapeutic efficacy. Pulmonary diseases are under worse scenarios as the altered physiological barriers generally induce stronger bio-nano interactions. To mitigate the bio-nano interactions and regulate the pulmonary fate of nanomedicines, a number of manipulating strategies were established based on size control, surface modification, charge tuning and co-delivery of mucolytic agents. Visualized and non-visualized characterizations can be employed to validate the robustness of the proposed strategies. This review provides a guiding overview of the physiological barriers affecting the in vivo fate of inhaled nanomedicines, the manipulating strategies, and the validation methods, which will assist with the rational design and application of pulmonary nanomedicine.

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