Since the French scientist Laufberger first separated ferritin from the spleen of a horse in 1937, research on ferritin has a history of nearly 90 years. Ferritin is an iron-storage protein that is widely present in organisms. Its biological function is mainly involved in iron metabolism and plays an important role in maintaining iron balance and cellular antioxidation. In eukaryotic cells, ferritin is usually a multimeric protein composed of 24 independent subunits. The subunit types include heavy chain ferritin (H subunit) and/or light chain ferritin (L subunit). These subunits can self-assemble to form highly ordered ferritin nanocages, with an outer diameter of 12 nm and an inner diameter of 8 nm. With its unique cage-like structure, each ferritin can store up to 4500 iron atoms in its cavity. Ferritin without iron core is called apoferritin, which is currently widely studied and applied as a drug carrier.
Fig. 1 The preparation of iron oxide nanoparticle loaded human HFn (M-HFn) (Song, N., et al. 2021).
Ferritin Drug Carrier (FDC)
Traditional nanocarriers for drug delivery have problems such as poor biocompatibility, low delivery efficiency, and high toxicity. Ferritin, as an endogenous natural protein in the human body, offers a new approach to drug delivery with its unique protein cage structure and self-assembly properties. With further research on ferritin, the concept of ferritin drug carriers (FDC) has gradually gained recognition and sparked a wave of research on ferritin in both basic research and clinical translation. Currently, ferritin drug carriers have successfully achieved efficient loading of various drug molecules, imaging agents, and metallic nanoparticles, and have been widely applied in biomedical fields such as in vivo delivery, biological imaging, disease diagnosis, and treatment.
Advantages of Ferritin Drug Carrier
- Cage-like spatial structure: Ferritin has a unique cage-like structure, and its internal cavity provides an ideal space for encapsulating drugs.
- Simple and efficient drug loading method: Ferritin nanocage has reversible self-assembly ability. Therefore, ferritin can effectively load drugs through the process of disassembly/reassembly of the protein cage.
- Intrinsic tumor targeting: Ferritin has natural tumor targeting. This gives ferritin drug carriers a unique advantage in tumor-targeted therapy.
- Functional modification: Ferritin can be expressed in Escherichia coli prokaryotes and is easily modified by genetic engineering to achieve functional design. In addition, lysine and cysteine residues on the outer surface of ferritin nanocage can be cross-linked with N-hydroxysuccinimide (NHS) ester or maleimide groups to chemically conjugate corresponding functional components. Therefore, the outer surface of ferritin can be functionally modified through genetic and chemical means according to application needs, thereby achieving specific targeting for different diseases and more diverse diagnostic and therapeutic functions.
- Excellent in vivo safety: As an endogenous protein, ferritin has the characteristics of low immunogenicity, high biocompatibility, and easy degradation. This ensures the safety of ferritin drug carriers during delivery in the body and lays the foundation for their translational applications in the biomedical field.
Ferritin as A Next-Gen Nucleic Acid Transporter
Compared to traditional drugs, nucleic acid drugs have the characteristics of clear therapeutic targets, simple preparation, and long-lasting and efficient effects, showing significant advantages in the treatment of tumors and genetic diseases. However, the application of nucleic acid drugs is severely limited by the problem of in vivo delivery, including the degradation of nucleic acids by nucleases in blood and tissues, the easy induction of immune clearance by exogenous nucleic acid molecules in the body, the hydrophilicity and negative charge of nucleic acids make it difficult for them to pass through the cell membrane and be taken up by cells, and it is difficult for nucleic acid drugs to effectively reach the target site after entering the cells. Undoubtedly, the development of nucleic acid drugs urgently requires safe and efficient nucleic acid delivery systems.
Ferritin is a nucleic acid carrier material with great application potential, which has high biological safety and low immunogenicity. However, the development of ferritin as a nucleic acid carrier is also limited by the natural negative charge of its protein structure, making it difficult to effectively load negatively charged nucleic acid drugs. In recent years, researchers have successfully constructed a positively charged inner cavity ferritin, HFn (+), which provides a safe and efficient novel in vivo delivery system for nucleic acid drugs.
Specifically, based on the analysis of the spatial structure of ferritin, researchers targeted the negatively charged amino acids - glutamic acid and/or aspartic acid located on the inner surface of ferritin. A series of lumen-positive ferritins with different mutation sites and numbers were constructed for the positively charged amino acids-lysine and/or arginine. Subsequently, researchers systematically evaluated and comprehensively considered the structural properties, self-assembly ability, nucleic acid loading performance, and stability of these mutants, and selected the HFn (+) mutant with the best loading efficiency and stability as a nucleic acid vector.
However, as an emerging potential candidate in nucleic acid carriers, the development of ferritin-nucleic acid carriers still faces many opportunities and challenges.
References
- 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.
- He, J.; et al. Ferritin drug carrier (FDC) for tumor targeting therapy. Journal of Controlled Release. 2019, 311: 288-300.
.
