The extensive alveolar capillary network of the lungs is an attractive route for the administration of several agents. One key functional attribute is the rapid onset of systemic action due to the absence of first-pass metabolism.

Here, we applied a combinatorial approach for ligand-directed pulmonary delivery as a unique route for systemic targeting in vaccination.

We screened a phage display random peptide library in vivo to select, identify, and validate a ligand (CAKSMGDIVC) that specifically targets and is internalized through its receptor, α3β1 integrin, on the surface of cells lining the lung airways and alveoli and mediates CAKSMGDIVC-displaying phage binding and systemic delivery without compromising lung homeostasis. As a proof-of-concept, we show that the pulmonary delivery of targeted CAKSMGDIVC-displaying phage particles in mice and non-human primates elicits a systemic and specific humoral response.

This broad methodology blueprint represents a robust and versatile platform tool enabling new ligand-receptor discovery with many potential translational applications.

Cancer Center Support Grants to the University of Texas M.D. Anderson Cancer Center (CA016672), University of New Mexico Comprehensive Cancer Center (CA118100), Rutgers Cancer Institute of New Jersey (CA072720), research awards from the Gillson-Longenbaugh Foundation, and National Institutes of Health (NIH) grant no. 1R01CA226537.