PEGylation of cationic, shell-crosslinked-knedel-like nanoparticles modulates inflammation and enhances cellular uptake in the lung

The airway provides a direct route for administration of nanoparticles bearing therapeutic or diagnostic payloads to the lung, however optimization of nanoplatforms for intracellular delivery remains challenging. Poly(ethylene glycol) (PEG) surface modification improves systemic performance but less is known about PEGylated nanoparticles administered to the airway. To test this, we generated a library of cationic, shell crosslinked knedel-like nanoparticles (cSCKs), including PEG (1.5. kDa PEG; 2, 5, 10 molecules/polymer arm) on the outer shell. Delivery of PEGylated cSCK to the mouse airway showed significantly less inflammation in a PEG dose-dependent manner. PEGylation also enhanced the entry of cSCKs in lung alveolar epithelial cells and improved surfactant penetration. The PEGylation effect could be explained by the altered mechanism of endocytosis. While non-PEGylated cSCKs used the clathrin-dependent route for endocytosis, entry of PEGylated cSCK was clathrin-independent. Thus, nanoparticle surface modification with PEG represents an advantageous design for lung delivery. From the Clinical Editor: In this study, the effects of PEGylation were studied on cross linked knedel-like nanoparticles in drug delivery through the lungs, demonstrating less airway inflammation in the studied model than with non-PEGylated nanoparticles, which suggests an overall favorable profile of PEGylated nanoparticles for alveolar delivery.