Smart nanoplatform with programmed release of dihydroartemisinin and Fe2+ self-supply for synergistic cancer therapy

Dihydroartemisinin (DHA) has caught worldwide attention as an innovative antitumor drug. However, the inherent defects of DHA reduce its transport efficiency in the bloodstream, and insufficient iron content in the tumor cells further leads to poor therapeutic efficacy. Therefore, it is highly desirable to exploit a DHA/Fe-loaded nanoplatform which releases its payload responding to the tumor microenvironment (TME). Herein, we reported the smart nanodrugs CaCO3@DHA@Fe3+-tannic acid (TA)@polyethylene glycol (PEG) (CDFP) nanoparticles (NPs) that specifically release DHA and self-supply Fe2+ ions at the tumor site for synergistic cancer therapy. Fe3+-TA shell with good photothermal performance makes CDFP NPs suitable photothermal agents for photothermal therapy (PTT). Once CDFP NPs were internalized by tumor cells, TA, Fe3+, DHA, and Ca2+ could be released in the acidic TME. And TA can reduce Fe3+ to Fe2+, followed by Fe2+-DHA mediated chemodynamic reaction to yield reactive oxygen species (ROS). Meanwhile, intracellular overloaded Ca2+ ions lead to the mitochondrial dysfunction, which increases ROS production and further induces tumor cell apoptosis. Such CDFP NPs with PTT, Fe2+-DHA mediated ROS, and Ca2+ overloading show excellent antitumor effects in vitro and in vivo, certifying their great potential in further clinical application.