Targeting nanoparticles to lung cancer-derived A549 cells based on changes on interstitial stiffness in biomimetic models.

The mechanical properties and forces of the extracellular environment modulate alveolar epithelial cell behavior. To model cancer/fibrosis associated stiffening and dynamic stretch, a biomimetic device was developed that imitates the active forces in the alveolus, while allowing control over the interstitial matrix stiffness. Alveolar epithelial A549 cancer cells were cultured on the devices and their transcriptome was profiled with RNA sequencing. Pathway analysis showed soft materials upregulated the expression of proteoglycans associated with cancer. Consequently, liposomes were modified with peptides targeting heparan sulfate and chondroitin sulfates of the cell surface glycocalyx. Chondroitin sulfate A targeting improved uptake in cells seeded on stiff biomimetic devices, which is attributed to increased chondroitin sulfate proteoglycan localization on cell surfaces in comparison to cells grown on soft devices. These results demonstrate the critical role that mechanical stiffness and stretch play in the alveolus and the importance of including these properties in nanotherapeutic design.