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Abstract
Ferritin (FRT) is a major iron storage protein found in humans and most living organisms. Each FRT is composed of 24 subunits, which self-assemble to form a cage-like nanostructure. The surface of FRT nanocage can be easily modified for tumor targeting and/or imaging. The interior of FRT can be loaded with different therapeutics. For example, we have used RGD-modified FRTs (RFRTs) to selectively deliver doxorubicin to tumors. The doxorubicin-loaded RFRTs showed improved tumor uptake, enhanced treatment efficacy, and reduced cardiotoxicity compared to free doxorubicin. The FRT nanocages can also be loaded with photosensitizers to facilitate photodynamic therapy (PDT). By choosing different targeting ligands, PDT can target different components in a tumor. For instance, folic acid-conjugated and ZnF16Pc-loaded FRTs can efficiently kill cancer cells in tumors. ZnF16Pc-loaded RFRTs, on the other hand, target tumor endothelium, and the impact is highly dependent on irradiation doses: at high irradiation doses, the enabled PDT causes vasculature collapse and blockage, leading to tissue ischemia; at low irradiation doses, PDT causes temporally enhanced vasculature permeability, which is beneficial to delivery of nanoparticles to tumors. More recently, we conjugated an anti-fibroblast activation protein (anti-FAP) scFv to ZnF16Pc-loaded FRTs and investigated the enabled PDT. The treatment efficiently killed cancer associated fibroblasts (CAFs) but left most cancer cells unharmed. Yet, efficient tumor growth suppression and extended survival was observed. Weve also developed a technology called red blood cell-facilitate PDT (RBC-PDT). In the RBC-PDT, we tether a large amount of photosensitizer-loaded FRTs to erythrocytes, which are natural O2 transporters. Because photosensitizers are located within an O2 rich zone on RBC membrane, they can efficiently produce 1O2 even when the overall oxygen level is low, for instance, in hypoxic tumor areas. This leads to efficient tumor therapy and represents a novel PDT approach. In summary, FRT-based drug delivery is a safe and efficient technology that holds great potential in clinical translation.