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. Author manuscript; available in PMC: 2014 Dec 23.
Published in final edited form as: ACS Nano. 2013 Nov 20;7(12):10597–10611. doi: 10.1021/nn404719c

Figure 10. Strategy of NSM-functionalization of drug carriers to bypass carrier size-restrictions and improve endocytosis.

Figure 10

ICAM-1-targeted nano- and micro-carriers are both efficiently internalized by cells due to sphingomyelinase (SMase)-dependent generation of ceramide at carrier-binding sites on the plasmalemma, which is associated with CAM-mediated endocytosis (left panel). Ceramide improves carrier engulfment and membrane invagination, and acts as a second messenger toward actin re-organization, helping in endocytosis. In contrast, targeting drug carriers to receptors associated with more size-restrictive pathways, e.g., clathrin-associated M6PR, often enables intracellular transport of nano- but not micro-carriers (middle panel). Surface-functionalization of said carriers with elements mimicking the CAM-mediated pathway, namely exogenous SMases (such as NSM in this study), does not impact binding but supplies ceramide and actin re-organization, improving endocytosis of nano- and micro-carriers even when targeted to receptors different from ICAM-1 (right panel).