Supramolecular Organization Predicts Protein Nanoparticle Delivery to Neutrophils for Acute Lung Inflammation Diagnosis and Treatment

Jacob W. Myerson; Priyal N. Patel; Nahal Habibi; Landis R. Walsh; Yi-Wei Lee; David C. Luther; Laura T. Ferguson; Michael H. Zaleski; Marco E. Zamora; Oscar A. Marcos-Contreras; Patrick M. Glassman; Ian Johnston; Elizabeth D. Hood; Tea Shuvaeva; Jason V. Gregory; Raisa Y. Kiseleva; Jia Nong; Kathryn M. Rubey; Colin F. Greineder; Samir Mitragotri; George S. Worthen; Vincent M. Rotello; Joerg Lahann; Vladimir R. Muzykantov; Jacob S. Brenner

The previous section demonstrates that two different nanoparticles based on protein, shown not to be denatured in CD spectroscopy studies, have uptake in LPSinflamed lungs driven by uptake in marginated neutrophils. We next undertook a broader study considering how aspects of NP structure including size, composition, surface chemistry, and structural organization impact NP uptake in LPS-injured lungs. As examples of different types of protein NPs, variants of LDNGs (representing NPs based on hydrophobic interactions between proteins), crosslinked protein NPs, and NPs based on electrostatic interactions between proteins were traced in naïve control and IV-LPS-injured mice. As examples of NPs based on site-specific protein interactions (rather than site-indiscriminate interactions leading to crosslinking, gelation, or chargebased protein NPs), we also traced viruses and ferritin nanocages in naïve and LPStreated mice. Liposomes and polystyrene NPs were studied as examples of lipid and polymeric nanostructures. Nanoparticles Based on Hydrophobic Protein Interactions LDNG size was varied by modifying lysozyme-dextran composition of the NPs and pH at which particles were formed. 42 Figure 2 , all sizes of LDNGs accumulated in LPS-injured lungs at higher concentrations than in naïve lungs, with accumulation in injured lungs reaching ~20% of initial dose for all types of LDNGs (Supplementary Table 3 ). Variations in size and composition of LDNGs therefore did not affect LDNG specificity for LPS-injured lungs.