Chemical
probes are key components of the bioimaging toolbox, as
they label biomolecules in cells and tissues. The new challenge in
bioimaging is to design chemical probes for three-dimensional (3D)
tissue imaging. In this work, we discovered that light scattering
of metal nanoparticles can provide 3D imaging contrast in intact and
transparent tissues. The nanoparticles can act as a template for the
chemical growth of a metal layer to further enhance the scattering
signal. The use of chemically grown nanoparticles in whole tissues
can amplify the scattering to produce a 1.4 million-fold greater photon
yield than obtained using common fluorophores. These probes are non-photobleaching
and can be used alongside fluorophores without interference. We demonstrated
three distinct biomedical applications: (a) molecular imaging of blood
vessels, (b) tracking of nanodrug carriers in tumors, and (c) mapping
of lesions and immune cells in a multiple sclerosis mouse model. Our
strategy establishes a distinct yet complementary set of imaging probes
for understanding disease mechanisms in three dimensions
