Aspect ratio determines the quantity of mesoporous silica nanoparticle uptake by a small GTPase-dependent macropinocytosis mechanism.

Although the aspect ratio (AR) of engineered nanomaterials (ENMs) is one of the key physicochemical parameters that could determine biological outcome, not much is understood about how AR contributes to shaping biological outcome. By using a mesoporous silica nanoparticle (MSNP) library that has been constructed to cover a range of different lengths, we could demonstrate that the AR of rod-shaped particles determines the rate and abundance of MSNP uptake by a macropinocytosis process in HeLa and A549 cancer cell lines. MSNPs with an AR of 2.1-2.5 were taken up in larger quantities compared to shorter or longer length rods by a process that is sensitive to amiloride, cytochalasin D, azide, and 4 °C inhibition. The rods with intermediary AR also induced the maximal number of filopodia, actin polymerization, and activation of small GTP-binding proteins (e.g., Rac1, CDC42) that involve assembly of the actin cytoskeleton and filopodia formation. When assessing the role of AR in the delivery of paclitaxel or camptothecin, the rods with AR 2.1-2.5 were clearly more efficient for drug delivery and generation of cytotoxic killing in HeLa cells. All considered, our data suggest an active sensoring mechanism by which HeLa and A549 cells are capable of detecting AR differences in MSNP to the extent that accelerated macropinocytosis can be used to achieve more efficient drug delivery.