Magneto-proteins: definition and mechanisms

Magneto-proteins are a class of naturally occurring or engineered proteins that respond to magnetic fields, enabling the remote modulation of cellular and neuronal processes. By combining magnetic sensitivity with biologically functional proteins, these constructs allow non-invasive and targeted control of intracellular signalling, gene expression, or ion channel activity. The main types of magneto-proteins include magnetoreceptors, magnetite-forming proteins, ferritin-based magneto-proteins, magnetosensory complex proteins, magnetogenetic actuators, and iron-sulphur cluster proteins [62].

The mechanisms underlying magneto-protein function include magnetothermal effects, in which iron-rich domains absorb energy from alternating magnetic fields to generate localized heating; mechanical torque, where magnetic domains exert forces on protein structures or ion channels; radical pair mechanisms, as observed in CRYs, where magnetic fields modulate spin-dependent biochemical reactions; and ion channel coupling, in which engineered fusion proteins link magnetic sensitivity directly to ionic fluxes and neuronal excitability [7].

Several notable magneto-proteins have been developed and characterized in recent years. Magneto, a synthetic fusion of the mechanosensitive ion channel TRPV4 and ferritin, enables magnetic-field-induced neuronal activation via calcium influx. The MagR complex, a naturally occurring magnetoreception assembly composed of the iron-sulphur cluster protein MagR and Cry4, is implicated in biological magnetosensing and has been adapted for bioengineering applications. Additionally, engineered ferritin variants with enhanced magnetic properties have been designed as versatile platforms for neuromodulation and targeted therapeutic delivery [7,63,64].

By harnessing their unique magnetic field-responsive properties, magneto-proteins offer a novel and versatile toolkit at the interface of molecular engineering, neuroscience, and nanomedicine, with significant potential for translational applications in neurodegenerative disorders such as AD and PD.

Magnetoreceptors

Magnetoreceptors are proteins or protein complexes that enable cells or organisms to detect and respond to magnetic fields. They function as biological sensors, converting magnetic field information into biochemical or electrical signals. The mechanisms underlying magnetic sensation in living organisms have been extensively studied. Magnetotactic bacteria, for example, synthesize single-domain magnetite crystals approximately 30 nm in size, each containing about one million iron atoms, and organize them into protein-based chains within the cell. The iron atoms interact strongly and align coherently in the same direction, forming a permanent magnetic dipole that functions as a miniature compass at room temperature. The long axis of the cell aligns with the external magnetic field, allowing the bacteria to navigate along magnetic field lines using their flagella [65,66].

Magnetic sensitivity in animals similarly relies on a compass-like mechanism. For instance, the attachment of a small magnetic crystal to a membrane ion channel can confer magnetic sensation. Alternatively, magnetic fields may act directly on specific biochemical reactions involving individual biomolecules. In this process, known as the “radical pair” mechanism, electron-transfer reactions generate radical pairs that can interconvert between singlet and triplet states. Magnetic fields can influence these electron transitions, thereby enabling organisms to detect magnetic fields [67,68].

In other organisms, a class of protein macromolecules acts as magnetoreceptors, first identified in the fruit fly and known as CRYs. These proteins form rod-shaped complexes containing approximately 40 iron atoms distributed along a length of 24 nanometers. Each complex possesses an intrinsic magnetic moment, large enough to align with the geomagnetic field (GMF). Although there is considerable interest in developing single-molecule magnets, their magnetic moments become unstable at temperatures above 14 K due to thermal fluctuations. Consequently, the amount of iron present in CRY proteins appears far below that required for stable magnetic behaviour at physiological temperatures [69].

For a long time, how living organisms sense and respond to the Earth’s magnetic field remained a subject of debate, until studies elucidated the mechanisms underlying the magnetic sensitivity of CRYs and the detection of GMFs in migratory birds and many other species. CRYs are intracellular flavoproteins that respond to UV-A or blue light. Two genes, CRY1 and CRY2, encode the corresponding CRY proteins, CRY1 and CRY2. CRYs are evolutionarily ancient and highly conserved, found across a wide range of organisms, from flies to birds and humans [70].

The magnetoreceptor complex formed by CRY flavoproteins consists of two functional modules: a light-sensing module and a magnetic-sensing module. The light-sensing module contains CRY proteins with conserved photolyase-related domains bound to the cofactor flavin adenine dinucleotide (FAD), located on the outer portion of the complex. The magnetic-sensing module is composed of MagR proteins, which contain iron-sulphur (Fe-S) centres positioned in the inner portion of the complex [63,71].

When exposed to blue or UV-A light, the FAD cofactor in CRYs transitions from its ground state to an excited state and is subsequently converted into flavosemiquinone forms (FAD•⁻ and FADH•). Electron transfer from the flavosemiquinone to adjacent conserved tryptophan residues generates long-lived tryptophan radical pairs. These electrons are then transferred from the tryptophan radicals to the Fe-S centres, ultimately forming a protein-based radical pair capable of exhibiting highly specific responses to magnetic fields [72,73].

Due to their pronounced sensitivity to the weak GMF, CRYs are regarded as biological compasses. These flavoproteins have been identified as key components in orientation, navigation, migration, and even reproduction in many birds, insects, and certain marine animals, such as whales [71].

CRYs mediate cellular responses to environmental stress by activating intracellular signalling pathways, thereby influencing key physiological, metabolic, and growth-related processes. They are expressed in all human cells and participate in indirect DNA repair pathways, contributing to the repair of UV-induced damage as well as the recognition and repair of DNA strand breaks. Notably, CRY expression levels are significantly higher in cancer cells compared to normal cells, and they are considered risk factors in various cancers, including breast, skin, lung, ovarian, prostate, and colorectal cancers [74-76].

CRYs possess the molecular features necessary to function as magnetic sensors. Genetic studies in invertebrates have confirmed the role of CRY in magnetosensation. Several behavioural studies in vertebrates have shown that extremely low-frequency electromagnetic fields, which influence electron spin states, can disrupt magnetic orientation. For example, Fedele et al. demonstrated that exposure to low-frequency electromagnetic fields (300 μT, 50 Hz) shortens the circadian period and induces hyperactivity in fruit flies-effects that disappear in the absence of CRY. Moreover, CRY is expressed in all major organs of birds and plays a role in regulating circadian rhythms in vertebrates.

Additional experiments have shown that fruit flies lacking CRY protein exhibit no magnetic orientation, further supporting the role of this protein in animal magnetoreception. Although CRY responds to magnetic fields via the radical-pair mechanism, the protein alone is theoretically insufficient to form a complete biological compass. Therefore, it is likely that an additional component works alongside CRY to enable organisms to detect and interpret the surrounding magnetic field [77].

Based on laboratory studies and in-silico analyses, the magnetic receptor within CRY-based magnetoreceptor complexes-referred to as MagR-is a rod-shaped protein around which the CRY protein is wrapped. This protein is structurally and magnetically unique, making it a particularly intriguing component of the magnetoreceptor complex. Although it is widely assumed that magnetic receptors are in the retinas of animals, there is no conclusive evidence that any specific cell type, such as cone photoreceptors, is directly sensitive to magnetic stimuli. In fact, both magnetite-based receptors and radical-pair-based receptors possess strong theoretical and experimental foundations, even though neither mechanism appears to be exclusive. Nevertheless, the evidence available across different species may support one hypothesis over the other depending on the organism [63].

Magnetic structure of cryptochromes

CRYs require linear polymerization with MagR proteins to sense the relatively weak GMF and function as a biological compass capable of detecting magnetic cues. The large hydrodynamic radii observed for both purified MagR proteins and CRY/MagR complexes in chromatographic analyses indicate the occurrence of polymerization. This polymerization, or the intrinsic self-assembly capacity of MagR, represents a critical feature of the magnetic-field sensing system. Such assembly may serve as an amplification mechanism in biological systems, enabling the detection of extremely weak magnetic fields, including the GMF [63].

The link between light sensing and magnetic reception is established through the interaction between CRY and MagR, whereby light-activated CRY is required to generate or modulate the biological compass. A study by Marley and colleagues demonstrated that inhibition of MagR gene expression disrupts circadian behaviour in fruit flies. Similar to observations reported for CRY, the effects of MagR on circadian resetting and light sensitivity suggest a functional connection between magnetoreception, light responsiveness, and circadian regulation. Furthermore, evidence indicates that this magnetoreceptor complex is localized within the cytoplasm, as none of its constituent proteins have been found to be membrane-associated [78].

The fully assembled CRY/MagR complex adopts a rod-like architecture in which the magnetic receptor MagR is positioned at the core, enabling the sensing of surrounding magnetic fields. The light-sensitive, rod-shaped CRY molecules are arranged around this central scaffold, functioning analogously to an antenna that receives optical stimuli. Experimental studies have shown that deletion of the conserved C-terminal helix of CRY markedly reduces the formation of the CRY/MagR complex. Similarly, removal of the iron-sulphur (Fe-S) clusters in MagR almost completely abolishes its interaction with CRY, indicating that these clusters are essential for proper assembly of the complex.

Within the 20-24 nm rod-like model of the CRY magnetoreceptor complex, 20 Fe-S clusters derived from 20 MagR monomers occupy the central region. Every four MagR subunits assemble into a disk-like unit containing four Fe-S clusters arranged in a ring, referred to as an “iron ring”-oriented perpendicular to the long axis of the magnetoreceptor. Two conserved helices of MagR are exposed on the polymer surface and adopt a ladder-like arrangement, serving as the primary interface for CRY binding through helix-helix interactions. The complete CRY/MagR complex comprises 20 MagR cores and 10 CRY molecules, indicating that polymer assembly is highly ordered and tightly regulated [63,67].

Radical pair model in cryptochromes

According to the radical pair model proposed by Ritz et al., magnetic field detection in living organisms is mediated by photochemically generated radical pairs, in which the flavin adenine dinucleotide (FAD) cofactor within CRY contains an electron with an unpaired spin. Upon photon excitation, these radical pairs are initially formed in a singlet state and can interconvert between singlet and triplet states under the influence of external magnetic fields. This singlet-triplet interconversion alters downstream chemical reaction pathways, thereby enabling organisms to extract directional information from the GMF [79].

The radical pairs generated through this mechanism are inherently unstable and may give rise to distinct chemical products, which ultimately influence navigational behaviour. Importantly, numerical and theoretical analyses have demonstrated that fluctuations in the GMF can modulate the efficiency and persistence of the singlet state, with the lifetime of this state being dependent on the orientation of the magnetic field. In addition, nuclear spins can generate local magnetic fields through hyperfine interactions and may therefore act as internal magnetic references. The magnitude of nuclear spin effects and dipole-dipole coupling between nuclear spins and the surrounding electron cloud are considered critical determinants of magnetic sensitivity in biological systems [67,79,80].

Although the radical pair model provides a compelling quantum-biological framework for magnetoreception, CRY alone is unlikely to generate a sufficiently robust signal to account for reliable magnetic sensing under physiological conditions. The extremely weak strength of the GMF, combined with thermal noise at body temperature and the transient lifetime of radical pairs, presents a significant challenge for direct neural encoding. From a neuroscience perspective, this limitation is particularly important, as magnetic information must ultimately be translated into changes in neuronal excitability, synaptic transmission, or network-level activity [81].

Consequently, additional molecular or structural components are thought to be required to amplify or stabilize magnetic signals before they can influence neuronal processes. Emerging experimental and computational evidence suggests that MagR may serve as such an amplification element by organizing CRY molecules into ordered polymeric assemblies and providing a magnetically responsive scaffold enriched with iron-sulphur (Fe-S) clusters. This cooperative structural arrangement may prolong radical pair lifetimes, enhance spin coherence, or generate localized magnetic fields capable of modulating CRY signalling [63].

Through this integrated mechanism, light-dependent radical pair chemistry is effectively coupled to MagR-based magnetic amplification, enabling weak environmental magnetic cues to be converted into biologically meaningful signals. This coupling provides a plausible pathway by which magnetic information can influence circadian regulation, orientation behaviour, and higher-order neural circuit function, thereby linking quantum-level spin dynamics to systems-level neuroscience phenomena [82,83].

Role of cryptochromes in regulating circadian rhythms

Circadian rhythms are intrinsic, endogenous cycles present in nearly all eukaryotic organisms. Through the regulation of biological clocks, these rhythms govern daily biochemical, physiological, and behavioural processes and are tightly synchronized with external geophysical cues, particularly the 24-hour light-dark cycle. Disruption of circadian regulation has been shown to adversely affect organismal fitness, and in animals, impaired circadian control is directly associated with reduced survival [84].

At the molecular level, CRYs function as core components of the transcription-translation feedback loop that underlies circadian oscillations. In mammals, CRY1 and CRY2 act as transcriptional repressors by interacting with PERIOD (PER) proteins and inhibiting CLOCK/BMAL1-mediated gene expression, thereby maintaining circadian periodicity and robustness of rhythmic gene expression (83). Genetic studies have demonstrated that CRY1 and CRY2 exert distinct regulatory effects on circadian timing: deletion of Cry1 or Cry2 differentially alters intrinsic circadian period length, whereas simultaneous loss of both proteins results in complete arrhythmicity [85,86].

Experimental evidence further suggests that the light-dependent oxidation of CRYs, leading to the formation of reduced flavin states, represents a potential initiating step in radical pair generation. This mechanism has been implicated in magnetic sensitivity and orientation behaviours in birds and fruit flies. In contrast, mammalian CRYs regulate circadian rhythms largely through light-independent pathways, underscoring fundamental species-specific differences in CRY signalling and functional integration with sensory inputs [87].

Beyond transcriptional regulation, CRYs also participate in post-transcriptional and post-translational control mechanisms that fine-tune circadian oscillations. Regulation of mRNA stability, protein turnover, and subcellular localization of CRY proteins contributes to the precision and adaptability of circadian rhythms across different tissues and developmental stages. Notably, developmental studies indicate that rhythmic CRY1 expression during early postnatal periods plays a critical role in establishing stable circadian period length later in life, highlighting an important link between circadian timing and neurodevelopment [88,89].

In mammals, CRYs exert their central regulatory functions in the suprachiasmatic nucleus (SCN), the brain's master circadian pacemaker. Within SCN neurons, CRYs influence electrophysiological depolarization, resting membrane potential, action potential firing, and neuronal responsiveness to photic input. Emerging evidence further suggests that CRYs may modulate neural sensitivity to GMF-related cues, providing a potential interface between circadian regulation, environmental magnetic signals, and neuronal excitability [90,91].

As essential components of the molecular circadian clock, CRYs regulate a broad range of biological processes beyond daily timekeeping, including cell cycle progression, DNA repair and replication, transcriptional control, and cellular growth and differentiation. Importantly, accumulating epidemiological and experimental data indicate that circadian disruption is associated with adverse health outcomes, such as sleep and mood disorders, metabolic syndrome, gastrointestinal diseases, and increased susceptibility to tumour initiation and progression. Dysregulation of CRY expression and function has been implicated in multiple cancer types, emphasizing their relevance to both neural homeostasis and disease pathogenesis [92,93].