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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 ironFerritin 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.

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.

Medical applications of nanotechnology typically focus on drug delivery and biosensors. Here, we combine nanotechnology and bioengineering to demonstrate that nanoparticles can be used to remotely regulate protein production in vivo. We decorated a modified temperature-sensitive channel, TRPV1, with antibody-coated iron oxide nanoparticles that are heated in a low-frequency magnetic field. When local temperature rises, TRPV1 gates calcium to stimulate synthesis and release of bioengineered insulin driven by a Ca²⁺-sensitive promoter. Studying tumor xenografts expressing the bioengineered insulin gene, we show that exposure to radio waves stimulates insulin release from the tumors and lowers blood glucose in mice. We further show that cells can be engineered to synthesize genetically encoded ferritin nanoparticles and inducibly release insulin. These approaches provide a platform for using nanotechnology to activate cells.

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.

Ferritin is a promising drug delivery platform and has been functionalized through genetic modifications. This work has designed and expressed a dual‐functional engineered human heavy‐chain ferritin (HFn) with the inserted functional peptide PAS and RGDK to extend half‐life and improve tumor targeted drug delivery. A facile and cost‐effective two‐step purification pathway for recombinant HFn was developed. The genetic modification was found to affect HFn conformation, and therefore varied the purification performance. Heat‐acid precipitation followed by butyl fast flow hydrophobic interaction chromatography (HIC) has been developed to purify HFn and modified HFns. Nucleic acid removal reached above 99.8% for HFn and modified HFns. However, HFn purity reached above 95% and recovery yield (overall) above 90%, compared with modified HFns purity above 82% and recovery yield (overall) above 58%. It is interesting to find that the inserted functional peptides significantly changed the molecule conformation, where a putative turnover of the E‐helix with the inserted functional peptides formed a “flop” conformation, in contrast with the “flip” conformation of HFn. It could be the cause of fragile stability of modified HFns, and therefore less tolerant to heat and acid condition, observed by the lower recovery yield in heat‐acid precipitation.

Hyperferritinaemia is a common laboratory finding that is often associated with metabolic dysfunction and fatty liver. Metabolic hyperferritinaemia reflects alterations in iron metabolism that facilitate iron accumulation in the body and is associated with an increased risk of cardiometabolic and liver diseases. Genetic variants that modulate iron homeostasis and tissue levels of iron are the main determinants of serum levels of ferritin in individuals with metabolic dysfunction, raising the hypothesis that iron accumulation might be implicated in the pathogenesis of insulin resistance and the related organ damage. However, validated criteria for the non-invasive diagnosis of metabolic hyperferritinaemia and the staging of iron overload are still lacking, and there is no clear evidence of a benefit for iron depletion therapy. Here, we provide an overview of the literature on the relationship between hyperferritinaemia and iron accumulation in individuals with metabolic dysfunction, and on the associated clinical outcomes. We propose an updated definition and a provisional staging system for metabolic hyperferritinaemia, which has been agreed on by a multidisciplinary global panel of expert researchers. The goal is to foster studies into the epidemiology, genetics, pathophysiology, clinical relevance and treatment of metabolic hyperferritinaemia, for which we provide suggestions on the main unmet needs, optimal design and clinically relevant outcomes.This Consensus Statement discusses the relationship between hyperferritinaemia and iron accumulation in individuals with metabolic dysfunction. The authors propose an updated definition and a provisional staging system for metabolic hyperferritinaemia, highlight research gaps and provide suggestions for the design and outcome measures for future studies.

The influence of nanoscale surface topography on protein adsorption is highly important for numerous applications in medicine and technology. Herein, ferritin adsorption at flat and nanofaceted, single-crystalline Al[sub.2]O[sub.3] surfaces is investigated using atomic force microscopy and X-ray photoelectron spectroscopy. The nanofaceted surfaces are generated by the thermal annealing of Al[sub.2]O[sub.3] wafers at temperatures above 1000 °C, which leads to the formation of faceted saw-tooth-like surface topographies with periodicities of about 160 nm and amplitudes of about 15 nm. Ferritin adsorption at these nanofaceted surfaces is notably suppressed compared to the flat surface at a concentration of 10 mg/mL, which is attributed to lower adsorption affinities of the newly formed facets. Consequently, adsorption is restricted mostly to the pattern grooves, where the proteins can maximize their contact area with the surface. However, this effect depends on the protein concentration, with an inverse trend being observed at 30 mg/mL. Furthermore, different ferritin adsorption behavior is observed at topographically similar nanofacet patterns fabricated at different annealing temperatures and attributed to different step and kink densities. These results demonstrate that while protein adsorption at solid surfaces can be notably affected by nanofacet patterns, fine-tuning protein adsorption in this way requires the precise control of facet properties.