In this work, we compare the role of two different uptake
mechanisms
in the effectiveness of a nanoformulated drug, specifically insulin.
Insulin is activated by interacting with insulin receptors exposed
on the liver cell membrane that triggers the uptake and storage of
glucose. To prove that the uptake mechanism of a delivery system can
interfere directly with the effectiveness of the delivered drug, two
extremely different delivery systems are tested. In detail, hydrogel-based
NPs (cHANPs) and natural lipid vesicles (EVs) encapsulating insulin
are used to trigger the activation of this hormone in 3D liver microtissues
(μTs) based on their different uptake mechanisms. Results demonstrated
that the fusion mechanism of Ins-EVs mediates faster and more pronounced
insulin activation with respect to the endocytic mechanism of Ins-cHANPs.
Indeed, the fusion causes an increased reduction in glucose concentration
in the culture medium EV-treatedl-μTs with respect
to free insulin-treated tissues. The same effect is not observed for
Ins-cHANPs that, taken up by endocytosis, can only equal the reduction
in glucose concentration produced by free insulin in 48 h. Overall,
these results demonstrate that the effectiveness of nanoformulated
drugs depends on the identity they acquire in the biological context
(biological identity). Indeed, the nanoparticle (NP) biological identity,
such as the uptake mechanism, triggers a unique set of nano-bio-interactions
that is ultimately responsible for their fate both in the extracellular
and intracellular compartments.