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[This corrects the article DOI: 10.1371/journal.pone.0336688.].

The ferritin nanocage is an endogenous protein that exists in almost all mammals. Its hollow spherical structure that naturally stores iron ions has been diversely exploited by researchers in biotherapeutics. Ferritin has excellent biosafety profiles, and the nanosized particles exhibit rapid dispersion and controlled/sustained release pharmacokinetics. Moreover, the large surface-to-volume ratio and the disassembly/reassembly behavior of the 24 monomer subunits into a sphere allow diverse modifications by chemical and genetic methods on the surface and inner cage of ferritin. Here, we critically review ferritin and its applications. We (i) introduce the application of ferritin in drug delivery; (ii) present an overview of the use of ferritin in imaging and diagnosis for biomedical purposes; (iii) discuss ferritin-based vaccines; and (iv) review ferritin-based agents currently in clinical trials. Although there are no currently approved drugs based on ferritin, this multifunctional protein scaffold shows immense potential in drug development in diverse categories, and ferritin-based drugs have recently entered phase I clinical trials. This golden shortlist of recent developments will be of immediate benefit and interest to researchers studying ferritin and other protein-based biotherapeutics. Ferritin: Delivering more than just iron Ferritin molecules, hollow protein spheres that store and release iron as needed, also hold promise for disease diagnosis, drug delivery, and vaccine development. Almost all organisms produce ferritin, which consists of 24 protein subunits that can interact with metals. Its biocompatibility, large surface-to-volume ratio, and ease of modification have led to investigation of its use in various medical applications, as reviewed by In-San Kim at the Korea Institute of Science and Technology in Seoul, South Korea, and co-workers. Ferritin can rapidly disperse, and release its contents steadily over a long time. It can deliver diagnostic imaging compounds or drugs to specific cells, or display antigens for immunotherapy or vaccines. Testing is underway for ferritin-based delivery of cancer drugs and development of vaccines for influenza, SARS-CoV-2, and diseases associated with Epstein Barr virus.

In the original publication [...]

In a multicenter, blinded end-point, open-label trial, adults undergoing maintenance hemodialysis were assigned to receive high-dose iron proactively or low-dose iron reactively. High-dose iron therapy was noninferior and led to lower doses of erythropoiesis-stimulating agent.

Ferritin (Ft) nanoparticles are promising scaffolds for antigen display in vaccine design due to their stability, defined architecture, and biocompatibility. Enzymatic methods, such as tyrosinase catalysis, enable covalent antigen conjugation by oxidizing tyrosine residues into o -quinones that react with accessible cysteine thiols. Here, we engineered Pyrococcus furiosus ferritin (PfFt) by introducing single cysteines at defined positions (K8C, D33C, and E92C) to enable site-specific bioconjugation. All PfFt variants retained their quaternary nanoparticle structure, as confirmed by mass spectrometry, dynamic light scattering, HPLC, and mass photometry. Thiol accessibility was verified by Ellman’s assay. Using tyrosinase-mediated catalysis, we conjugated two tyrosine-tagged antigens, Rift Valley fever virus Gn and SARS-CoV-2 receptor-binding domain, to the engineered cysteines. Up to 13 antigens were displayed per 24-mer nanoparticle. Conjugation was highly specific to the engineered cysteines, and the resulting antigen-PfFt conjugates bound neutralizing antibodies with nanomolar affinities (2–7 nM), comparable to their soluble antigen counterparts. This work establishes a robust and modular strategy for precise antigen display on ferritin nanocages using tyrosinase-mediated cysteine conjugation. The platform shows strong potential for next-generation protein-based vaccines and other bioconjugate therapeutics.

The incidence of type 2 diabetic osteoporosis (T2DOP), which seriously threatens elderly people’s health, is rapidly increasing in recent years. However, the specific mechanism of the T2DOP is still unclear. Studies have shown the relationship between iron overload and T2DOP. Mitochondrial ferritin (FtMt) is a protein that stores iron ions and intercepts toxic ferrous ions in cells mitochondria. Ferroptosis, an iron-dependent cell injured way, may be related to the pathogenesis of T2DOP. In this study, we intend to elucidate the effect of FtMt on ferroptosis in osteoblasts and explain the possible mechanism. We first detected the occurrence of ferroptosis in bone tissue and the expression of FtMt after inducing T2DOP rat model. Then we used hFOB1.19 cells to study the influence of high glucose on FtMt, ferroptosis, and osteogenic function of osteoblasts. Then we observed the effect of FtMt on ferroptosis and osteoblast function by lentiviral silencing and overexpression of FtMt. We found ferroptosis in T2DOP rats bone. Overexpression of FtMt reduced osteoblastic ferroptosis under high glucose condition while silent FtMt induced mitophagy through ROS / PINK1/Parkin pathway. Then we found increased ferroptosis in osteoblasts after activating mitophagy by carbonyl cyanide-m-chlorophenyl-hydrazine (CCCP, a mitophagy agonist). Our study demonstrated that FtMt inhibited the occurrence of ferroptosis in osteoblasts by reducing oxidative stress caused by excess ferrous ions, and FtMt deficiency induced mitophagy in the pathogenesis of T2DOP. This study suggested that FtMt might serve as a potential target for T2DOP therapy.