Molecular Mechanisms and Biomedical Applications of Ferritin Nanocages: A Comprehensive Review of Self-Assembly, Engineering, and Multifunctional Delivery Platforms

Abstract: Ferritin is a heteropolymer or homopolymer composed of 24 polypeptides forming a cage-shaped sphere. Its main function is to maintain soluble and non-toxic states of iron ions in the body. In mammals, ferritin is primarily located in the cytoplasm and the mitochondria. Cytoplasmic ferritin consists of heavy (H) and light (L) subunits, whereas mitochondrial ferritin is a homopolymer composed exclusively of a single subunit type. A notable feature of ferritin is its ability to self-assemble into nanocages in vitro, which is reversible and controllable. This unique property has enabled its widespread application in various fields including drug delivery, disease diagnosis, and vaccine development. In this review, we provide a comprehensive overview of ferritin, focusing on the following aspects: 1) structural characteristics, biological functions, dynamics, and molecular mechanisms underlying ferritin self-assembly, 2) recent advances and applications of ferritin-based self-assembled nanocages in biomedicine and bioengineering, and 3) progress in the molecular modification of ferritin using genetic engineering techniques. Additionally, we critically examined the current limitations of ferritin in research and practical applications, and proposed potential strategies for further improvement, with the aim of providing insights into the future development and utilization of ferritin in medical and scientific contexts. This work integrates the kinetics and molecular mechanisms of ferritin self-assembly with advanced genetic engineering strategies, offering a systematic framework for the rational design of ferritin-based multifunctional platforms. The infographic illustrates various aspects of ferritin. In the center, ferritin is depicted with its structure labeled. Surrounding it are four sections: Sources, Application, Modification and Self-assembly. The Sources section includes images of a mouse, silkworm, frog, bacteria and plant, indicating diverse biological origins. The Application section highlights uses such as drug and metal ion delivery, genetic fusion for vaccines and cell targeting. The Modification section shows size-constrained reaction vessels and chimeric assembly. The Self-assembly section illustrates different molecular assemblies labeled M2, M4, M6, M12 and M24, showing the progression from smaller to larger structures. Each section is visually connected to the central ferritin structure, emphasizing its versatility and importance in various scientific fields.Infographic on ferritin showing sources, applications, modifications and self-assembly processes. Keywords: ferritin, self-assembly, nanocage, nanomedicine, drug delivery