Structurally, 12 pairs of ferritin subunits group in antiparallel orientations to form a regular dodecahedron with 4–3-2 axial symmetry. Each cylindrical subunit (5 nm length × 2.5 nm diameter) contains four α-helical bundles (antiparallel A–B and C–D pairs) and a shorter C-terminal α-helix (E). Helix E forms a 60° angle with the B–C helices, connected via an 18-residue non-helical BC loop. Surface charge distribution is distinctive: at neutral pH, the inner surface exhibits high negative charge density due to acidic residues (e.g., Glu, Asp), while the outer surface (comprising subunit N-termini, BC loops, and A/C helices) carries a slight positive or neutral net charge. Critically, each ferritin molecule contains eight threefold-axis channels and six fourfold-axis channels (3–5 Å pore diameter), forming a network that connects the protein cavity to the external environment (2, 23–25). This unique cage architecture allows cells to precisely regulate iron ion supply.

Regarding subunit composition, vertebrate ferritin primarily comprises heavy (H-type) and light (L-type) chains. Plant-derived ferritin exhibits distinct subunit characteristics: its light chains differ significantly from homopolymeric heavy chains, and molecular weights vary across sources. For example, soybean seed ferritin subunits are 26.5 kDa (H-1) and 28.0 kDa (H-2), markedly larger than their vertebrate counterparts (19.0 kDa light chain; 21.0 kDa heavy chain) (26). Mammalian ferritin typically consists of ~21 kDa heavy (H) and ~19.5 kDa light (L) chains, sharing 55% amino acid sequence similarity. The H-subunit harbors a binuclear ferroxidase center with conserved iron-binding sites (Glu27, Tyr34, Glu62, His65, Glu107, Gln141) responsible for rapid Fe²⁺ oxidation. As a prototypical pore protein, ferritin possesses six fourfold-, eight threefold-, and 12 twofold-axis channels (0.3–0.5 nm pore diameter) (2).

Ferritin’s reversible disassembly/reassembly driven by pH facilitates efficient encapsulation of bioactives. Its thermostability enables cost-effective production and purification in Escherichia coli, outperforming other nanocarriers. Under extreme acidity or alkalinity (pH ≤ 2.0 or ≥ 11.0), the cage disassembles into subunits; reassembly occurs at neutral pH. Composed of non-toxic elements, ferritin rarely elicits strong non-self-antibody responses. Its ferroxidase site (nucleation center) binds iron and other metal ions and can be functionally modified via chemical or genetic conjugation (27–30). This approach efficiently encapsulates molecules too large to diffuse through intact cage pores. Leveraging reversible self-assembly, numerous nutrients, drugs, and functional molecules have been successfully loaded into ferritin nanocages (30–34).

Ferritin, a multifunctional protein ubiquitous in bacteria, plants, and animals, has been extensively studied for its iron storage and detoxification roles (2). Structural studies reveal that >90% of iron in legume seeds is stored as ferritin (35). Compared to prokaryotes (which contain heme-bearing bacterioferritins, BFRs, and canonical H-type ferritins) and vertebrates, plant ferritin (phytoferritin) displays unique traits. Subcellularly, animal ferritin localizes to the cytoplasm, with expression tightly regulated by iron response elements (IREs) and iron regulatory proteins (IRPs) (36). In contrast, plant ferritin resides in plastids and is primarily transcriptionally regulated (37, 38). Although primary amino acid sequences lack homology, secondary, tertiary, and quaternary structures show significant conservation, indicating evolutionary preservation. In apoferritin cages, light subunits dominate (80–90%), while heavy subunits comprise 10–20%; sequence homology between them is 55%. Hydrophilic channel sequences are identical, but outer surface, cavity, and hydrophobic channel sequences differ (39, 40).

Ferritin source selection depends on application requirements. Plant-derived ferritin, with unique L-subunits and functional properties, excels in specific contexts. Animal-derived ferritin, with well-defined structure and established iron storage function, holds promise for biomedicine and therapy. Vertebrate-derived ferritin, with clear H/L subunit differentiation and high sequence similarity (55%), provides an ideal model for research and therapeutic development (41). Optimal ferritin types should be selected based on functional needs, as sources offer distinct advantages.

Sturgeon liver ferritin, a biomacromolecule with unique spatial conformation, demonstrates significant value in food science, biomedicine, and nanotechnology. Its 24 subunits self-assemble into a spherical nanocage (~12 nm diameter; ~8 nm cavity) as defined in Table 1, with highly symmetric architecture observable via transmission electron microscopy (TEM). Subunits are classified as H-type (≈20.5–21.1 kDa) and L-type (≈20.2–20.8 kDa), separable by SDS-PAGE. Fourier-transform infrared (FTIR) and circular dichroism (CD) spectra reveal a secondary structure dominated by α-helices (52.79–72.16%), supplemented by β-sheets, turns, and random coils. This conformational synergy confers environmental adaptability (42, 43). The protein maintains structural stability between 60 and 80°C and pH 3.4–10; beyond these thresholds, α-helix unfolding causes functional decline. These characteristics are further illustrated through a comparison in Table 2.

Sturgeon ferritin demonstrates remarkable pH-responsive behavior, maintaining structural stability across a wide pH range (3.4–10), making it particularly suitable for oral delivery systems, functional foods, and encapsulation technologies. The protein subunits (SLF-1, SLF-2, and SLF-3) undergo reversible dissociation at extreme pH conditions while retaining the ability to reassemble at neutral pH. This unique property facilitates efficient encapsulation and targeted release of sensitive bioactive compounds, including antioxidants and therapeutic agents, throughout the gastrointestinal tract (43). Notably, the ferritin maintains stability under both gastric (pH 2–3) and intestinal (pH 6–7) conditions, effectively preventing premature degradation.

The exceptional pH tolerance enables incorporation into diverse food matrices, ranging from acidic beverages (pH 3.5–4.5) to alkaline food products (pH 8–9). Nutritionally, sturgeon ferritin provides substantial value with its high amino acid content (>600 mg/g) and balanced essential amino acid profile (SLF-1 meets FAO/WHO standards), while simultaneously serving as an effective iron-chelating agent that maintains structural integrity during fortification processes (43, 44).

The protein’s hollow nanocage architecture, combined with its pH-dependent assembly properties, allows for simultaneous encapsulation of both hydrophilic and hydrophobic bioactive compounds, including polyphenols and vitamins (44). Comparative studies by Ding. (42) demonstrate that sturgeon ferritin exhibits superior structural preservation during pH fluctuations compared to plant-derived ferritins.

Ferritin nanocages serve as versatile biological templates for chemotherapy drug encapsulation, photothermal therapy, and in vivo imaging. Beyond drug delivery, loading with metal nanoparticles and dye molecules enables optical and magnetic resonance imaging (MRI), providing critical support for early cancer detection, diagnostic subtyping, treatment monitoring, and prognostic assessment as depicted in Figure 5. The 12-nm size of sturgeon liver ferritin facilitates tumor targeting via the enhanced permeability and retention (EPR) effect, elevating intratumoral drug concentration while reducing systemic toxicity in murine models.

Digestive stability of ferritin in the gastrointestinal tract critically determines its efficacy for nutrient and drug delivery. Nanoparticles failing to withstand digestive conditions lose therapeutic value (25). Ferritin’s unique advantages include: its protein cage shields against complexation by dietary factors (e.g., phytic acid, oxalate, tannins); natural seed coat protection confers gastric stability; and its slow-release iron core fundamentally differs from conventional iron supplements (inorganic/organic salts) and natural chelates (e.g., Fe(III)-phytate) in physicochemical behavior (73).

The ferritin cavity functions as a nanoreactor for precise synthesis of functional materials (e.g., magnetic Fe₃O₄). Polyethylene glycol (PEG) surface modification extends in vivo circulation half-life, while quantum dot hybrids combine structural stability with fluorescence for advanced bioimaging. Compared to conventional synthesis, ferritin-templated technology confers superior monodispersity and functional programmability to nanomaterials (30, 43, 74).

While ferritin is recognized as an effective dietary iron source for iron-deficient populations, its bioavailability remains a subject of debate. Conflicting results have been reported, particularly regarding iron absorption from plant-based ferritins such as soybean ferritin. Nonetheless, several studies have demonstrated that ferritin-bound iron is bioavailable and can contribute meaningfully to alleviating iron deficiency. For instance, the bioavailability of iron from pea ferritin has been validated in dietary trials, and ferritin-delivered iron has been shown to be comparable in absorption to traditional iron salts like ferrous sulfate, especially in non-anemic individuals (75, 76).

The variability in outcomes may be attributed to several influencing factors, including physiological conditions, dietary composition, and ferritin origin or structural differences (76). Radioisotope-based studies, which are commonly employed to assess iron absorption, have revealed inconsistencies. Early in vitro and in vivo experiments using radiolabeled ferritin reported contrasting results particularly with legume seed ferritin, where nearly 90% of seed iron was stored as ferritin, yet showed limited bioavailability in exogenously labeled studies (77). A major limitation stems from the challenges of uniform radiolabeling in vivo, which can result in incomplete tagging of ferritin iron and lead to differential absorption of unlabeled iron. These methodological discrepancies complicate accurate evaluation of ferritin’s true bioavailability. Given its nutritional importance, especially for combating global iron deficiency, resolving these inconsistencies is critical. Future research should prioritize advanced radiolabeling and stable isotope techniques, structural modification of the ferritin shell through genetic engineering, and the development of encapsulation approaches to more precisely track and enhance ferritin iron absorption.

Ferritin functions not only as an iron status biomarker but also as a key indicator of inflammation. Altered glycosylation patterns during inflammatory and oncologic processes offer novel avenues for early diagnosis (62, 78). Inflammatory cytokines upregulate H-and L-subunit expression at transcriptional and translational levels (79). When iron demand surges or deficiency occurs, stored iron must be mobilized primarily via lysosomal protease-mediated ferritin degradation (80). Autophagy mechanisms participate in this process, with recent studies identifying nuclear receptor coactivator 4 (NCOA4) as a cargo receptor mediating targeted lysosomal degradation of ferritin, termed ferritinophagy (89). Progressive elevation of ferritin and other inflammatory markers consistently correlates with disease severity and mortality (81–84).

Future ferritin research must focus on several critical areas. The primary task involves deepening mechanistic understanding of ferritin structural stability, particularly its dynamic behavior in complex food matrices and during digestion, while systematically elucidating molecular pathways of iron release and absorption to resolve controversies surrounding iron bioavailability.

For application bottlenecks in food engineering, innovative uses in fresh-cut fruit shelf-life extension should be prioritized, including: mechanistic investigation into how ferritin-encapsulated antioxidants (e.g., ascorbate, polyphenols) inhibit enzymatic browning and oxidative deterioration; development of smart coatings or targeted delivery systems (incorporating sturgeon liver ferritin) for controlled release of actives on cut surfaces; comprehensive evaluation of ferritin carriers’ effects on sensory quality (color/texture/flavor), microbial safety, and retention of key nutrients (e.g., vitamin C, polyphenols) in fresh-cut produce; and tackling stability challenges in high-water-activity, complex-matrix food systems.

Concurrently, systematic assessment of long-term intake safety including potential immunogenicity, metabolic pathways, and chronic toxicity requires strengthening. Industrially, scaling production processes (e.g., efficient sturgeon ferritin extraction/purification) is urgently needed to significantly reduce costs and increase yields. Parallel efforts should expand ferritin’s cross-disciplinary applications in precision nutrition delivery, tumor-targeted therapy, inflammatory disease intervention, and stimuli-responsive materials.

Current clinical translation faces dual challenges: prohibitive extraction costs and insufficient long-term safety evidence. Future advancements necessitate breakthroughs in scalable production technologies and establishing an integrated “basic research → technology development → industrial application” framework through interdisciplinary collaboration to fully unlock ferritins potential across food engineering, biomedicine, and materials science.