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 EditorIn 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.

Graphical AbstractWe constructed a library of cationic nanoparticles (cSCK, 20-30 nm diameter) with a hydrophobic core and highly functionalizable cross-linked shell. The effect of cSCK with differing shell surface modifications was studied with the goal to identify the least toxic nanocarrier capable of intracellular uptake when delivered to the airway. Only mice that received cSCK possessing a surface rich in poly(ethylene glycol) (PEG) showed minimal inflammatory response, comparable to saline control. Furthermore, PEGylation enhanced nanoparticle uptake in the lung, specifically alveolar epithelial type II cell (shown within box). These responses were PEG concentration-dependent and associated with a shift in endocytic mechanism.Figure optionsDownload high-quality image (169 K)Download as PowerPoint slide