Chemodynamic therapy (CDT) utilizes iron-initiated Fenton chemistry to destroy tumor cells by converting endogenous H O into the highly toxic hydroxyl radical ( OH). There is a paucity of Fenton-like metal-based CDT agents. Intracellular glutathione (GSH) with OH scavenging ability greatly reduces CDT efficacy. A self-reinforcing CDT nanoagent based on MnO is reported that has both Fenton-like Mn delivery and GSH depletion properties. In the presence of HCO , which is abundant in the physiological medium, Mn exerts Fenton-like activity to generate OH from H O . Upon uptake of MnO -coated mesoporous silica nanoparticles (MS@MnO NPs) by cancer cells, the MnO shell undergoes a redox reaction with GSH to form glutathione disulfide and Mn , resulting in GSH depletion-enhanced CDT. This, together with the GSH-activated MRI contrast effect and dissociation of MnO , allows MS@MnO NPs to achieve MRI-monitored chemo-chemodynamic combination therapy.

Ferritin is a major iron storage protein found in humans and most living organisms. Each ferritin is comprised of 24 subunits, which self-assemble to form a cage-like nanostructure. FRT nanocages can be genetically modified to present a peptide sequence on the surface. Recently, we demonstrated that Cys-Asp-Cys-Arg-Gly-Asp-Cys-Phe-Cys (RGD4C)-modified ferritin can efficiently home to tumors through RGD integrin αvβ3 interaction. Though promising, studies on evaluating surface modified ferritin nanocages as drug delivery vehicles have seldom been reported. Herein we showed that after being pre-complexed with Cu(II), doxorubicin can be loaded onto RGD modified apoferritin nanocages with high efficiency (up to 73.49wt%). When studied on U87MG subcutaneous tumor models, these doxorubicin-loaded ferritin nanocages showed a longer circulation half-life, higher tumor uptake, better tumor growth inhibition, and less cardiotoxicity than free doxorubicin. Such a technology might be extended to load a broad range of therapeutics and holds great potential in clinical translation.

The advancements, perspectives, and challenges in blood–brain-barrier (BBB)-crossing nanotechnology for effective brain tumor delivery and highly efficient brain cancer theranostics.