Breaking the threshold of intracellular
reactive oxygen species
(ROS) levels can cause nonspecific oxidative damage to proteins and
lead to the Fenton reaction-mediated exogenous ROS production to be
a new promising anticancer strategy. However, the problems, including
the inefficient transport of metal catalysts and insufficient endogenous
hydrogen peroxide (H2O2) content in cells, still
need to be improved. In this study, a functional nanosystem encapsulated
with benzothiazole complexes (FeTB2) and the photosensitizer
indocyanine green (ICG) was designed for highly effective antitumor
therapy. The surface of the nanocarriers was modified with dihydroartemisinin
(DHA)-grafted polyglutamic acid. The induced hyperthermia enables
the lipid–polymer shell to depolymerize, releasing FeTB2. The released FeTB2 could kill tumor cells in
two different ways by inhibiting DNA replication and catalyzing H2O2 to produce active •OH. Moreover, the
conjugated DHA could increase the amount of peroxides in tumor cells
and significantly enhance the ROS yield. This work has provided solid
evidence that the present nanosystem enables a significant effect
on tumor killing through the combined inhibition of DNA replication
and ROS-mediated oxidative damage by regulation of the tumor microenvironment,
providing a ROS-mediated high-efficiency antitumor strategy.