The intracellular spherical iron storage protein ferritin consists of 24 subunits which separate into heavy chain ferritin (HFn) and light chain ferritin (LFn). Ferritin functions as a globular protein found within animal, plant and microbial cells to store and release iron ions. The unique structure and excellent biocompatibility of ferritin combined with its functional modifiability have turned it into an emerging nanoplatform for drug delivery in recent studies.
Several therapeutic drugs such as cisplatin, carboplatin, paclitaxel, curcumin, atropine, quercetin, gefitinib, daunorubicin, epirubicin and doxorubicin among others have been used as cargo molecules to date. Scientists have successfully incorporated therapeutic drugs, fluorescent dyes and radioisotopes for medical imaging along with MRI contrast agents as well as siRNA and miRNA nucleic acids into ferritin nanocages along with various metal nanoparticles such as Fe3O4 and CeO2. The lumen of ferritin nanocages has been used to encapsulate various cargo molecules for biomedical applications which span in vitro biosensing to targeted biological system delivery using genetically or chemically modified targeting ligands.
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Ferritin Structure and Basic Properties
Structural Features
Ferritin is composed of 24 subunits, forming a hollow spherical shell with a diameter of about 12 nm and an internal cavity of about 8 nm. The inner cavity can be used to encapsulate drugs, metal ions or other molecules. There are multiple functional sites on the surface of the subunits, which are convenient for chemical modification and ligand connection.
Biocompatibility
Ferritin is naturally derived and has low immunogenicity. It can be specifically taken up by cells through receptor-mediated means (such as TfR1 receptor).
Physiological Functions
Ferritin plays a physiological role in the body mainly by regulating iron metabolism, and its activity involves a variety of life processes:
Iron Storage and Release
Ferritin can store up to 4,500 iron ions (Fe³⁺) to regulate intracellular iron homeostasis. When there is an excess of iron ions, ferritin captures free iron to prevent the iron-catalyzed Fenton reaction from producing free radicals and protect cells. When the demand for iron increases, ferritin can release Fe²⁺ for cell use through ferroreductase.
Antioxidant Effect
Free iron promotes the generation of ROS (reactive oxygen species), and ferritin "seals" iron ions to prevent oxidative damage. It has a protective effect on tissues under conditions of inflammation, hypoxia or stress.
Immunomodulatory Function
Ferritin can affect macrophage polarization and T cell activity. Some subtypes (such as H-chain ferritin) have signal transduction functions in the immune system.
Effects on Cell Proliferation and Differentiation
Ferritin indirectly affects the cell cycle, DNA synthesis and differentiation processes by regulating the availability of iron.
Fig 1. Ferritin is a typical nanoplatform for drug delivery (Song, N., et al. 2021).
Advantages of Ferritin in Drug Delivery
| Features |
Advantages |
| Strong targeting |
Can enter tumor cells through transferrin receptor (TfR1) |
| Stable structure |
Stable to acid, base and heat, suitable for a variety of pathological environments |
| Can load multiple drugs |
Can encapsulate small molecule drugs, nucleic acids, metal ions, etc. |
| Easy to modify the surface |
Ligands can be modified by genetic engineering or chemical methods |
| Controllable release |
pH sensitivity allows it to release drugs in the tumor microenvironment |
Drug Loading Method
- Cavity encapsulation: opening the ferritin shell by changing pH or ionic strength to load the drug into the cavity.
- Surface covalent attachment: chemically attaching drugs or targeting ligands to the ferritin surface.
- Genetic engineering embedding: embedding drug binding sites into subunits through protein engineering.
Ferritin for Drug Delivery
Ferritin has been widely studied as a natural protein nanocarrier, particularly suitable for targeted drug delivery systems.
Targetability
Transferrin receptor 1 (TfR1) which shows high expression levels on numerous cancer cells allows ferritin to enter cells. Due to this property ferritin possesses the innate capability to target tumors.
Intelligent Responsive Release
Ferritin demonstrates sensitivity to both pH levels and temperature variations as well as enzyme environments. This system releases therapeutic agents only within tumor sites like low pH conditions which helps to minimize damage to healthy tissues.
Application Examples
| Type |
Drugs |
Function |
| Antitumor |
DOX, cisplatin, paclitaxel |
Targeted delivery, improved efficacy, reduced toxicity |
| Gene therapy |
siRNA,mRNA |
Stable transport, improved transfection efficiency |
| Imaging |
Gd³⁺, fluorescent probes |
MRI/optical imaging |
| Antibacterial/antiviral |
Silver ions, interferon |
Targeted infected cells |
- Anticancer drug delivery: The introduction of chemotherapy drugs like doxorubicin (DOX) and cisplatin into ferritin enables targeted cancer treatment delivery to tumors.
- RNA/DNA delivery: The inner cavity serves as a container for siRNA or mRNA molecules in gene therapy applications.
- Imaging and diagnosis: Tumor imaging uses fluorescent probes or magnetic nanoparticles as loaded materials.
- Immunotherapy carrier: Transport immunomodulators or antigens to stimulate an immune response.
Development Prospects
- Combined with artificial intelligence and synthetic biology, designing "intelligent ferritin nanorobots"
- Expanding applications in transmembrane delivery, blood-brain barrier penetration, etc.
- Multimodal diagnosis and treatment integrated platform (Theranostics)
Application Areas
- Biomaterials and nanomedicine
- Protein engineering and carrier design
- Tumor targeting and immune microenvironment regulation
- Optimization direction of drug delivery system design
Optimization Direction of Drug Delivery System Design
- Remodeling ferritin subunit structure to improve drug loading efficiency
- Covalent modification of targeting ligands to enhance specific recognition ability
- Construction of combined treatment platform to achieve integrated diagnosis and treatment (such as ferritin + photothermal agent + drug)
- Integration of exogenous response system, such as photosensitive/magnetic/thermosensitive ferritin nanoparticles
References
- Plays, M., et al. Chemistry and biology of ferritin. Metallomics. 2021, 13(5): mfab021.
- Song, N., et al. Ferritin: a multifunctional nanoplatform for biological detection, imaging diagnosis, and drug delivery. Accounts of chemical research. 2021, 54(17): 3313-3325.
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