Fluorophores
with multifunctional properties known as rare-earth-doped
nanoparticles (RENPs) are promising candidates for bioimaging, therapy,
and drug delivery. When applied
in vivo
, these nanoparticles
(NPs) have to retain long blood-circulation time, bypass elimination
by phagocytic cells, and successfully arrive at the target area. Usually,
NPs in a biological medium are exposed to proteins, which form the
so-called “protein corona” (PC) around the NPs and influence
their targeted delivery and accumulation in cells and tissues. Different
surface coatings change the PC size and composition, subsequently
deciding the fate of the NPs. Thus, detailed studies on the PC are
of utmost importance to determine the most suitable NP surface modification
for biomedical use. When it comes to RENPs, these studies are particularly
scarce. Here, we investigate the PC composition and its impact on
the cellular uptake of citrate-, SiO
2
-, and phospholipid
micelle-coated RENPs (LiYF
4
:Yb
3+
,Tm
3+
). We observed that the PC of citrate- and phospholipid-coated RENPs
is relatively stable and similar in the adsorbed protein composition,
while the PC of SiO
2
-coated RENPs is larger and highly
dynamic. Moreover, biocompatibility, accumulation, and cytotoxicity
of various RENPs in cancer cells have been evaluated. On the basis
of the cellular imaging, supported by the inhibition studies, it was
revealed that RENPs are internalized by endocytosis and that specific
endocytic routes are PC composition dependent. Overall, these results
are essential to fill the gaps in the fundamental understanding of
the nano-biointeractions of RENPs, pertinent for their envisioned
application in biomedicine.