Ferritin: A Multifunctional Nanoplatform for Biological Detection, Imaging Diagnosis, and Drug Delivery

Abstract

Metrics & MoreArticle Recommendations CONSPECTUS: Ferritins are spherical iron storage proteins within cells that are composed of a combination of 24 subunits of two types, heavy-chain ferritin (HFn) and light-chain ferritin (LFn). They autoassemble naturally into a spherical hollow nanocage with an outer diameter of 12 nm and an interior cavity that is 8 nm in diameter. In recent years, with the constantly emerging safety issues and the concerns about unfavorable uniformity and indefinite in vivo behavior of traditional nanomedicines, the characteristics of native ferritin nanocages, such as the unique nanocage structure, excellent safety profile, and definite in vivo behavior, make ferritin-based formulations uniquely attractive for nanomedicine development. To date, a variety of cargo molecules, including therapeutic drugs (e.g., cisplatin, carboplatin, paclitaxel, curcumin, atropine, quercetin, gefitinib, daunomycin, epirubicin, doxorubicin, etc.), imaging agents (e.g., fluorescence dyes, radioisotopes, and MRI contrast agents), nucleic acids (e.g., siRNA and miRNA), and metal nanoparticles (e.g., Fe 3 O 4 , CeO 2 , AuPd, CuS, CoPt, FeCo, Ag, etc.) have been loaded into the interior cavity of ferritin nanocages for a broad range of biomedical applications from in vitro biosensing to targeted delivery of cargo molecules in living systems with the aid of modified targeting ligands either genetically or chemically. We reported that human HFn could selectively deliver a large amount of cargo into tumors in vivo via transferrin receptor 1 (TfR1)-mediated tumor-cell-specific targeting followed by rapid internalization. By the use of the intrinsic tumor-targeting property and unique nanocage structure of human HFn, a broad variety of cargo-loaded HFn formulations have been developed for biological analysis, imaging diagnosis, and medicine development. In view of the intrinsic tumor-targeting property, unique nanocage structure, lack of immunogenicity, and definite in vivo behavior, human HFn holds promise to promote therapeutic drugs, diagnostic imaging agents, and targeting moieties into multifunctional nanomedicines.Since the report of the intrinsic tumor-targeting property of human HFn, we have extensively explored human HFn as an ideal nanocarrier for tumor-targeted delivery of anticancer drugs, MRI contrast agents, inorganic nanoparticles, and radioisotopes. In particular, by the use of genetic tools, we also have genetically engineered human HFn nanocages to recognize a broader range of disease biomarkers. In this Account, we systematically review human ferritins from characterizing their tumor-binding property and understanding their mechanism and kinetics for cargo loading to exploring their biomedical applications. We finally discuss the prospect of ferritin-based formulations to become next-generation nanomedicines. We expect that ferritin formulations with unique physicochemical characteristics and intrinsic tumor-targeting property will attract broad interest in fundamental drug research and offer new op...

Ferritin Conjugates With Multiple Clickable Amino Acids Encoded by C-Terminal Engineered Pyrrolysyl-tRNA Synthetase

“…In the field of drug delivery, protein cages are employed to prolong the half-life of drugs, exert enhanced permeability and retention effect, reduce nonspecific uptake by introducing targeting ligand, and enhance drug solubility or endocytosis effect ( Zhang et al, 2021 ). For instance, Ftn is applied to the delivery of enzymes ( Tetter and Hilvert, 2017 ; Uchida et al, 2018 ) and chemotherapy drugs ( Ahn et al, 2018 ; Song et al, 2021 ).…”

“…For recognition purposes, the embedded targeting motifs are usually designed to be genetically fused to the N-terminus of Ftn, which allows 24 targeting motifs exposed on the Ftn surface to specifically recognize the target expressed on cells. The modified Ftn has been applied in cancer therapies ( Song et al, 2021 ; Zhang et al, 2021 ).…”

Application Perspectives of Nanomedicine in Cancer Treatment

“…According to the characteristics of ferritin nanocages, metal-based chemotherapeutic drugs such as carboplatin and cisplatin are the first to achieve effective precipitation in the cavity of iron nanocages. Subsequently, ferritin nanocages have also been used to load other non-metallic chemotherapeutic drugs such as doxorubicin ( Song et al, 2021 ). Here we list the applications of ferritin in the delivery of chemotherapeutic drugs in Table 3 .…”

Surface-Fabrication of Fluorescent Hydroxyapatite for Cancer Cell Imaging and Bio-Printing Applications

“…Multifunctional nanoparticles are of great interest for new applications such as cell imaging, drug delivery and tumor therapy [ 1 , 2 , 3 , 4 , 5 ]. Increasing surface chemistry strategies are used to establish these nanosystems via surface modification, such as polymer surface coating and small molecule surface grafting [ 6 , 7 , 8 ].…”