  Precise localization of nanoparticles within a cell is crucial to the
understanding of cell-particle interactions and has broad applications in
nanomedicine. Here, we report a proof-of-principle experiment for imaging
individual functionalized nanoparticles within a mammalian cell by correlative
microscopy. Using a chemically-fixed, HeLa cell labeled with fluorescent
core-shell nanoparticles as a model system, we implemented a graphene-oxide
layer as a substrate to significantly reduce background scattering. We
identified cellular features of interest by fluorescence microscopy, followed
by scanning transmission X-ray tomography to localize the particles in 3D, and
ptychographic coherent diffractive imaging of the fine features in the region
at high resolution. By tuning the X-ray energy to the Fe L-edge, we
demonstrated sensitive detection of nanoparticles composed of a 22 nm magnetic
Fe3O4 core encased by a 25-nm-thick fluorescent silica (SiO2) shell. These
fluorescent core-shell nanoparticles act as landmarks and offer clarity in a
cellular context. Our correlative microscopy results confirmed a subset of
particles to be fully internalized, and high-contrast ptychographic images
showed two oxidation states of individual nanoparticles with a resolution of
~16.5 nm. The ability to precisely localize individual fluorescent
nanoparticles within mammalian cells will expand our understanding of the
structure/function relationships for functionalized nanoparticles.
