Lanthanide carriers: biomedical imaging redefined

Abstract

Lanthanide-based carriers have emerged as powerful platforms for next-generation biomedical imaging, combining unique optical and magnetic features to address key limitations of conventional agents. Owing to their 4f electron configuration, lanthanide ions provide sharp emission lines, long lifetimes, high photostability, and strong paramagnetism, enabling high-resolution, multiplexed, and deep-tissue imaging with minimal photodamage. This review surveys recent advances across optical, X-ray, and magnetic resonance modalities, focusing on how material design influences performance. We examine representative carriers, such as lanthanide-doped nanoparticles, organic complexes, and lanthanide-binding proteins, and their roles in near-infrared (NIR) imaging (long-term single-particle tracking, molecular sensing, and NIR-II modalities), X-ray imaging (contrast media, scintillators, and persistent emitters for low-dose diagnostics), and magnetic resonance imaging (chemical and biosynthetic agents with enhanced relaxivity, specificity, and safety, including targeted protein constructs). We highlight molecular engineering and surface modification strategies that boost signal and biocompatibility, and discuss emerging directions such as artificial intelligence-enabled data analysis and the integration of multimodal probes to deliver integrated anatomical and functional information. While most advances are still at the proof-of-concept stage, lanthanide carriers show great potential for bridging materials science, biophysics, and clinical needs, and are reshaping biomedical imaging toward more precise, responsive, and personalized diagnostics.

Key points

Introduction

Biomedical imaging is essential in modern diagnostics, underpinning nearly every stage of the clinical care pathway, from early disease diagnosis and treatment planning to image-guided intervention and therapeutic evaluation (1). By enabling non-invasive visualization of anatomical, physiological, and molecular processes, imaging techniques have transformed our ability to understand, monitor, and treat diseases. Modalities such as magnetic resonance imaging (MRI), computed tomography (CT), positron emission tomography (PET), and optical imaging (e.g., fluorescence and bioluminescence) have greatly advanced clinical decision-making and outcomes (2). Beyond clinical practice, these techniques are also indispensable in preclinical biomedical research, where they enable the study of disease mechanisms and tracking of therapeutic agents. Nonetheless, current imaging modalities still face trade-offs between penetration depth, spatial resolution, sensitivity, and long-term in vivo tracking (2, 3). Many techniques cannot reliably detect early or subtle pathological changes or track biological processes over extended periods due to limited probe stability, radiation exposure, or photobleaching.

Lanthanides (Ln), often dubbed the “vitamins of industry” (4), underpin numerous advances in biomedicine and other high-tech industries. Sometimes misleadingly referred to as “rare earth” elements, Ln are f-block metals characterized by progressive filling of the 4f orbitals from lanthanum to lutetium. Ln-based materials address many of the aforementioned gaps in biomedical imaging through properties rooted in their 4f manifolds (5–7). Their 4f transitions yield sharp, well-defined emission peaks and long lifetimes that support time-gated, multiplexed optical imaging with minimal photodamage (5). These combined attributes enable high sensitivity, specificity, and functional versatility across modalities (Figure 1) (7). Beyond small-molecule chelates, engineered platforms such as Ln-doped nanoparticles, metal–organic frameworks (MOFs), and Ln-binding proteins offer improved biocompatibility, multifunctionality, and targeting.

Figure 1

Here, we review recent advances in Ln carriers for biomedical imaging, spanning molecular imaging, in vivo optical imaging, X-ray imaging, and MRI. Particular attention is given to design principles, imaging performance, and translational considerations. We highlight how key Ln features, such as their long lifetimes and environmental sensitivity, enable improved detection sensitivity, quantitative sensing, and integrated imaging readouts. We further discuss the emerging role of artificial intelligence (AI) in data analysis and probe discovery, offer pragmatic perspectives on multimodality, and address sustainability concerns. Together, these advances are improving imaging sensitivity, contrast, and multimodal functionality while redefining how biological information is detected and interpreted. Despite this progress, clinical translation remains constrained by issues including long-term safety, clearance, manufacturability, and regulatory requirements. Finally, we outline current challenges and future opportunities, aiming to provide interdisciplinary insights that will drive the continued evolution of Ln-based technologies toward more precise, effective, and personalized healthcare solutions and deeper biological discoveries.

Current lanthanide carriers

Ln carriers have been extensively developed to improve the stability, solubility, and biological performance of Ln-based systems. Current designs include inorganic nanomaterials, small-molecule chelators, and emerging biomolecular platforms such as peptides and proteins. Each category offers distinct coordination environments, that is, unique ways of binding and surrounding the Ln ion, and functional advantages that determine the overall imaging or therapeutic efficacy. This section introduces fundamental properties of Ln and summarizes the major types of Ln carriers currently explored.

Photophysical and magnetic properties

Ln share similar chemical behavior, typically adopt the trivalent state, and possess unique magnetic, optical, and electronic properties. Ln ions are well suited to biomedical imaging (8). Their 4f–4f transitions are parity-forbidden and only weakly allowed through 5d/ligand-field mixing, resulting in intrinsically small Stokes shifts because both absorption and emission originate from the same 4f manifolds. The exceptional sharpness of these transitions arises from the strong shielding of 4f electrons by the more radially extended 5s and 5p subshells, a feature that critically affects processes such as non-radiative energy transfer between Ln ions (9). Reports of large Stokes shifts in Ln probes usually arise from ligand-to-metal sensitization (antenna effect), charge‐transfer states, cross‐relaxation, or down/upconversion cascades rather than vibronic relaxation within a single transition (5, 8). To avoid ambiguity, the term “pseudo‐Stokes shift” is used when emission follows sensitization or energy migration instead of direct 4f absorption. Long excited‐state lifetimes (µs to ms), narrow line-like spectral bands, and high photostability enable time-gated detection, multiplexing, and prolonged imaging by minimizing photobleaching and signal overlap. Ln-doped nanomaterials can also provide upconversion, i.e., converting near-infrared (NIR) excitation to visible emission, which supports deep-tissue imaging with minimal photodamage (5, 7). Emission characteristics remain tunable via the coordination environment and host matrix.

Magnetically, unpaired 4f electrons confer strong paramagnetism, making them useful for MRI (10, 11). Gadolinium (Gd³⁺; highest magnetic moment among the lanthanide ions) is ideal for T₁-weighted contrast (e.g., Gd-DTPA, the Gd³⁺ chelate of diethylenetriaminepentaacetic acid), whereas dysprosium (Dy³⁺), holmium (Ho³⁺), and erbium (Er³⁺) exhibit large anisotropy favoring T₂-weighted imaging (e.g., Er³⁺-doped nanoparticles) (12). Stable incorporation into tailored carriers enables tunable magnetic behavior and targeted applications.

Local coordination environment

The local coordination environment surrounding Ln ions plays a decisive role in defining their physicochemical, optical, and magnetic properties. Subtle variations in ligand type, geometry, and hydration number can strongly influence parameters such as brightness, emission quantum yield, energy transfer dynamics, and relaxivity. In the context of Ln carriers, rational control over the coordination microenvironment is therefore essential to optimize stability, minimize quenching, and tailor performance for imaging or therapeutic applications.

Radiative rates (Judd–Ofelt)

Radiative rates in Ln complexes are strongly influenced by the local coordination environment, which governs the electric-dipole 4f–4f transition probabilities. According to Judd–Ofelt theory, the empirical parameters (Ω₂, Ω₄, and Ω₆) can quantify local coordination and permit estimates of radiative lifetimes and branching ratios (13, 14). Hypersensitive transitions, e.g., europium (Eu³⁺) ⁵D₀→⁷F₂ and Dy^{3+ 4}F_9/2→⁶H_13/2, are especially diagnostic of ligand changes (15, 16). This highlights the link between molecular structure and macroscopic imaging performance, providing insight into how tailored coordination environments can improve brightness, color purity, and contrast in Ln-based systems.

Non-radiative pathways

High-energy X–H oscillators near the Ln ion (O–H ≈ 3,500 cm^–1 > N–H > C–H) accelerate multiphonon relaxation, a vibration-driven non-radiative decay process, thereby quenching emission. Such quenching, in which excited-state energy is lost without producing light, reduces luminescence intensity and lifetime, thereby limiting the brightness and sensitivity of Ln-based probes in imaging applications. Its impact can be minimized with low-phonon hosts (e.g., fluorides), hydrophobic or thicker passivation shells, or deuteration (17). While crystal-field variations only weakly perturb 4f levels, they strongly affect 5d states [cerium (Ce³⁺) and Eu²⁺] and antenna triplets/charge-transfer states, thereby opening or closing quenching channels (12, 18). More broadly, the local environment modulates emission probability: displacing coordinated solvent with a bound guest can reduce non-radiative quenching, increasing luminescence intensity and lifetime. Conversely, new quenching pathways may appear. A notable special case is Eu³⁺: if the ligand-to-metal charge-transfer states are located close to the emissive ⁵D₀ level, quenching ensues; moreover, the hypersensitive ⁵D₀→⁷F₂ band reports coordination changes via pronounced intensity shifts relative to other bands (19, 20).

Magnetism and relaxivity (MRI)

Coordination geometry tunes magnetic anisotropy and water access. The inner-sphere hydration number q is set by ligand denticity/rigidity. Optimizing water exchange (k_ex), rotational correlation time (τ_R), and electron-spin relaxation maximizes relaxivity (21). Relaxivity (r₁ or r₂) quantifies the efficiency with which a paramagnetic ion enhances the relaxation of nearby water protons, directly dictating image brightness and contrast in MRI. Maximizing these parameters through coordination design has therefore become central to improving the sensitivity and diagnostic performance of Ln-based MRI agents.

Representative lanthanide carriers

Owing to the evident toxicity of free heavy metal ions arising from their competition with physiological calcium (Ca²⁺) for binding sites, various types of Ln carriers have been developed to chelate the free ions for biomedical applications (12, 22).

Lanthanide-doped nanocrystals

When Ln ions are incorporated into inorganic host lattices (typically fluorides or oxides), they support upconversion or downshifting to produce emission from the ultraviolet (UV) to the NIR spectral region (6). Upconversion nanoparticles (UCNPs), which absorb two or more low-energy NIR photons and emit higher-energy light, are especially attractive for biological imaging because NIR excitation reduces tissue scattering and autofluorescence, allowing for deep tissue penetration and high contrast (7, 23). This feature makes UCNPs highly promising for biophotonics, including real-time in vivo imaging, single-particle tracking, and time-gated detection (24, 25). Moreover, their exceptional photostability compared with organic dyes or fluorescent proteins also favors long-term imaging. In the complementary downshifting mode, neodymium (Nd³⁺), Er³⁺, or thulium (Tm³⁺) centers emit in NIR-I (700–950 nm) and NIR-II (1,000–1,700 nm) after UV or X-ray excitation via 4f–4f transitions, minimizing tissue absorption, scattering, and autofluorescence (26). This emission profile is particularly advantageous for deep-tissue imaging, as it minimizes light scattering and absorption. X-ray responsive nanoparticles can also function as scintillators for clinical examination (27).

To maximize signal quality and stability in vivo, Ln nanocrystals are typically engineered with core–shell architectures (written core@shell in material formulae). An undoped, lattice-matched shell (~3–5 nm) separates activators from surface oscillators, suppressing quenching and cross-relaxation and often boosting brightness and lifetime by an order of magnitude (7, 28). Moreover, active shells can direct energy flow from sensitizers to emitters, manage dopant concentration, and enable avalanche (i.e., strong, nonlinear signal amplification) while limiting back-transfer (i.e., energy flowing backward from emitters to sensitizers) (29, 30). These effects enhance luminescence brightness and imaging sensitivity, enabling clearer visualization in deep-tissue or single-particle imaging. Shells also improve colloidal and biological stability, resisting ligand exchange, protein adsorption, and acid etching. They also provide robust anchors for stealth/targeting coronas—coatings such as polyethylene glycol (PEG) and zwitterions that minimize immune recognition and present ligands for selective cell binding—without compromising optics (31). Such stabilization minimizes aggregation and nonspecific interactions in vivo, thereby prolonging circulation time and improving imaging contrast and reliability.

Lanthanide–organic complexes

Ln complexes are highly promising luminescent probes owing to their sharp emission bands, long lifetimes, and effective ligand-to-metal sensitization (“antenna effect”) that overcomes low intrinsic 4f absorption (17, 32). The absorbed energy is transferred from the ligand’s triplet state, or from its first excited singlet state, to the excited state of the Ln ion, resulting in efficient, photostable emission (33). Emission spans the visible [Eu³⁺ and terbium (Tb³⁺)] to NIR [Nd³⁺ and ytterbium (Yb³⁺)] spectra, enabling deep-tissue optical readouts (17). The shielded 4f orbitals confer spectral stability and resistance to photobleaching. For biomedical use, complexes must be water-soluble, stable, and preferably excitable >400 nm. Modern ligand designs now support targeted, responsive, and even therapeutic imaging functions (34). These features make Ln complexes well suited to high-contrast, time-resolved, and multiplexed imaging in both research and clinical contexts.

Lanthanide-binding proteins

Biological Ln carriers, such as proteins, peptides, and biomimetic scaffolds, provide well-defined, engineerable coordination sites for high-affinity, site-specific binding (35–38). Genetic programmability (e.g., mutagenesis, fusion tags, and responsive motifs) enables functional customization, improving metal-binding specificity, loading, targeting, and circulation while mitigating limitations of small-molecule chelators (e.g., poor aqueous stability, short half-life, off-target accumulation, and potential toxicity) (39, 40). Their nanoscale dimensions and modularity facilitate targeted delivery, cellular uptake, and multimodal signal integration. Recent work demonstrates utility across MRI, X-ray, and optical modalities, positioning Ln-binding proteins as versatile platforms for precise diagnostics and theranostics (37).

Applications in near-infrared imaging

Upon optical excitation in the near-infrared (NIR-I/NIR-II) windows, Ln ions generate sharp, spectrally tunable emissions for high-resolution molecular sensing and deep-tissue imaging. These emissions arise from parity-forbidden 4f–4f transitions, which confer narrow bandwidths, long excited-state lifetimes, and remarkable photostability compared with conventional organic dyes or fluorescent proteins. NIR excitation minimizes tissue absorption and autofluorescence, establishing Ln emitters as powerful tools for visualizing biological processes with high spatial and temporal precision.

Upconversion-enabled long-term tracking and molecular probing

Owing to their excellent photostability and ultralow autofluorescence interference, UCNPs have been employed for long-term single-particle tracking and real-time readout of local physical signals, including temperature, force, and water status (Figure 2). NIR excitation reduces tissue scattering and background autofluorescence, enabling deep, high-contrast imaging suitable for biophotonics applications including super-resolution, time-gated detection, and in vivo tracking (24, 41, 42).

Figure 2

Neural tracking

Axonal transport distributes organelles, vesicles, and signals between soma and synapses, and its dysregulation is tightly linked to neurodegeneration (43, 44). Conventional probes (fluorescent proteins and quantum dots) are limited by photobleaching and blinking, and visible-light autofluorescence compromises contrast. Enabling wide-field, deep, background-suppressed tracking, UCNPs have revealed transport defects associated with the neurodevelopmental disorder Rett syndrome in human induced pluripotent stem cell-derived neurons (45) and early neurotoxicity signatures via machine-learning analysis of transport parameters (42). They have also identified nanometer-precision cargo trajectories over millimeter distances, including stochastic changes in dynein motor number and a two-step adenosine triphosphate (ATP)-dependent stepping cycle (25). Beyond passive readout, UCNPs can drive optogenetic modulation by emitting opsin-matched wavelengths under NIR, enabling wireless, transcranial control of deep circuits and demonstrating therapeutic effects including dopamine release and seizure suppression (46, 47).

Mechanosensors

Mechanical forces ranging from piconewtons (pN) to micronewtons (μN) regulate immune cell migration, adhesion, and differentiation; tissue remodeling; neuronal signaling; and muscle contraction (48, 49). Traditional methods such as atomic force microscopy, optical tweezers, traction microscopy, and fluorescent sensors trade off invasiveness, depth, and dynamic range (50). UCNP-based mechanosensors address these limits: Tm³⁺-doped photon-avalanche nanoparticles report forces from ~620 pN to 1.7 µN, converting weak stimuli into strong emissions via steep, nonlinear responses and offering mechanobrightening and mechanochromic readouts tunable by dopant concentration (51). In parallel, ingestible UCNP microgauges embedded in polystyrene spheres can quantify intraluminal forces in vivo. For example, in the Caenorhabditis elegans pharynx, these microgauges recently exhibited a linear 0.4–15.2 µN calibration and visualized ~10–15 µN muscular contractions during feeding, enabling synchronized optical–electrophysiological studies of neuromuscular dynamics across aging, genetics, and pharmacology (52). Together, these platforms provide scalable, photostable, and remotely addressable force sensing from cellular to tissue scales.

Nanothermometers

Temperature is a critical regulator of biology, affecting enzyme kinetics, metabolism, and organelle function (53). For instance, mitochondrial heat generation during ATP production tracks metabolic state, motivating accurate thermometry for disease research and therapy (54). Traditional tools, such as infrared cameras and thermocouples, lack subcellular resolution or penetration (55–58), necessitating novel approaches.

Ln upconversion nanothermometers exploit thermally coupled energy levels to convert temperature changes into spectral ratios or lifetime shifts, enabling quantitative, ratiometric maps at the microscale (59). Designs operating in the NIR-III window (1,500–2,000 nm) minimize scattering for deeper imaging (60, 61). Such systems can resolve temperature variations within micron-scale cerebrovascular structures, providing a powerful means to probe brain microcirculation and offering potential insights for disease diagnosis and therapeutic intervention. Examples include Sr₂LuF₇:Yb³⁺–Ho³⁺–Er³⁺ nanoparticles with sensitivities up to 9% K^–1 under tissue-mimicking conditions (62), NaYF₄:Nd³⁺/Yb³⁺ ceramics for lifetime-encoded NIR-II imaging with ~0.01°C^–1 sensitivity (63), and in vivo ratiometric nanoparticles achieving ~0.1 K resolution (64). Surface-engineered probes extend to organelle-level thermometry. Mitochondria-targeted nanoparticles reported in situ mitochondrial dynamics (65), while a LysoDots/MitoDots map coordinated lysosome–mitochondrion responses to stress and drugs (66). Immune cell-anchored core–shell NaGdF₄:Yb/Er@NaGdF₄ probes revealed a ~38°C threshold for Ca²⁺ influx and CD69 activation, with 1.4% K^–1 sensitivity from the 525/545 nm ratio (67). Reliable luminescent thermometers have also been developed in the form of core–shell heater–thermometer nanoparticles comprising a γ‐Fe₂O₃ core coated with a polymeric shell embedded with samarium (Sm³⁺)- and Eu³⁺-based complexes. These particles enable temperature measurements under exposure to an alternating magnetic field (60). A surface temperature increase of up to 8°C was observed on the nanoheaters, with negligible heating at the cell membrane. Even under magnetically safe conditions, these local temperature increases were sufficient to induce slight but noticeable cell death, which became pronounced at the maximum field intensity permitted for human use, demonstrating the feasibility of localized hyperthermia for targeted tumor therapy. Carrasco et al. developed Nd³⁺-doped LaF₃ nanoparticles that act simultaneously as heaters and luminescent nanothermometers for in vivo photothermal therapy (68). The particles enable real-time intratumoral temperature readout via the ratiometric 865/885-nm emission, revealing that internal tumor temperatures exceed surface values by ~20%. This study established a self-reporting nanoplatform for precise, feedback-controlled thermal therapy.

Beyond inorganic nanocrystals, lanthanide complexes enable compact ratiometric thermometers. Encapsulated Eu³⁺/Sm³⁺ complexes reached ~0.1°C intracellular sensitivity and linked temperature dynamics to Ca²⁺ transport (69). Recently, a host–guest calcium-based MOF embedding Tb³⁺/Eu³⁺ provided tunable dual emission across 160–380 K, with enhanced sensitivity via optimized ion ratios and transfer pathways (70).

In all cases, intracellular thermometry relies on pre-established calibration curves (spectral or lifetime vs. temperature), a strategy that could extend to other parameters given sufficiently sensitive calibrations. However, two caveats remain. First, achieving ~0.1°C precision is challenging with conventional materials and analysis. AI-assisted spectral–temporal modeling may help but requires further validation. Second, buffer-derived calibrations often drift inside cells due to sensitivity to local hydration, pH, viscosity, and ionic strength. This underscores the need for in situ calibration and careful cross-validation, as identical thermal responses in solution and cells have yet to be firmly established.

Water probing

Water serves as the solvent and reaction medium for virtually every biological process, and its local organization and dynamics critically influence biomolecular behavior. The hydration status of proteins is crucial for understanding their structure, stability, dynamics, and function (71). Water molecules play active roles in mediating protein folding, conformational changes, molecular recognition, and catalytic activity (71–73)—processes that are closely linked to disease progression and treatment response. From a biomedical perspective, monitoring protein hydration provides fundamental insights into biological mechanisms and supports the development of therapeutic interventions (72). However, conventional techniques, such as X-ray crystallography, cryo-electron microscopy, and nuclear magnetic resonance (NMR), provide only static snapshots of protein structures and cannot capture real-time water movement in living systems. Indirect methods such as cell volume measurements or Raman spectroscopy suffer from low sensitivity and poor temporal resolution, making them unsuitable for tracking the fast and subtle dynamics of water in biologically relevant environments. These limitations underscore the need for alternative strategies capable of probing local hydration dynamics in situ with high spatiotemporal precision.

Upconversion luminescence offers a valuable option to probe local hydration dynamics through its intrinsic sensitivity to the local coordination environment. In particular, high-energy O–H vibrational modes (~3,400 cm^–¹) of nearby water molecules can strongly couple with the excited states of Ln ions, promoting non-radiative multiphonon relaxation and thereby quenching luminescence. This effect is highly distance- and density-dependent, enabling luminescence intensity and lifetime to serve as sensitive reporters of local water content and hydration changes. Early mechanistic studies demonstrated that upconversion emission can be quenched by ~99% in water but not in heavy water (D₂O), establishing a vibrational quenching pathway (74). Subsequent research moved beyond treating water solely as a quencher to leveraging this sensitivity as a quantitative readout of water content and transport, turning Ln luminescence into a sensitive tool for water sensing. Core–shell and core–shell–shell architectures were designed to shield the sensitizer while retaining an analyte-responsive outer layer, enabling ratiometric or lifetime-encoded water sensing at the single-particle level. A representative example is ligand-free NaYF₄:Yb/Er nanoparticles, whose nonlinear emission is exquisitely quenched by trace water in organic solvents, enabling optical detection to 0.008 vol% (80 ppm). By simultaneously tracking lanthanide-to-O–H energy transfer and 980 nm excitation attenuation, Guo et al. created a ratiometric, reusable sensor capable of real-time, in situ, and even non-contact water detection (75). Importantly, this hydration sensitivity extends into biological systems. Recent studies employing core–shell–shell UCNPs have enabled direct visualization of D₂O/H₂O exchange across membrane channels, including aquaporin-1 and transient receptor potential cation channel subfamily V member 1 (TRPV1), in living cells. This technique directly quantified water flux through biological channels at the single-cell and single-molecule level and revealed solvent-mediated modulation of ion channel activity and a previously unrecognized route for analgesic regulation (76, 77).

In addition to nanoparticles, Fueyo-González et al. developed two families of small-molecule Ln antennas based on quinolinone derivatives that selectively sensitize Eu³⁺ or Tb³⁺ luminescence and exhibit strong quenching in the presence of water (78). These Ln complexes function as highly sensitive optical sensors for trace water detection in organic solvents, with detection limits below 0.03%. Wang et al. reported an upconversion luminescent humidity sensor based on an yttrium (Y)/Yb/Er-doped MOF that exhibits dual emission at 500 nm and 660 nm under 980 nm excitation, enabling ratiometric detection of relative humidity from 11% to 95% (79). The sensor shows excellent linearity, reversibility, and cycle stability (>93% recovery), demonstrating the potential of lanthanide-doped MOFs for reliable optical water detection in complex biomedical scenarios. Together, these studies demonstrate that water–Ln interactions provide a robust physicochemical basis for sensing water content through luminescence modulation rather than directly imaging water molecules. By exploiting hydration-dependent quenching effects, these systems enable sensitive optical readouts of local hydration changes that are difficult to access using conventional techniques.

Notably, most Ln probe studies remain at the proof-of-concept stage, and challenges including quantitative accuracy in complex biological environments, probe stability, and rigorous in vivo validation still need to be addressed. In contrast, established optical probes (e.g., organic dyes and fluorescent proteins) continue to dominate routine biological imaging due to their standardized protocols (80–82). Thus, the advantages of Ln systems are most pronounced in specialized applications that require long-term stability, deep penetration, or ultrasensitive sensing. These translational and quantitative challenges are closely linked to fundamental performance limitations, as discussed below.

Performance limits and validation

Intracellular sensing often defies buffer-based calibrations because the cytoplasm’s crowded macromolecular environment alters refractive index, viscosity, and ionic strength, which in turn shifts spectral and lifetime readouts. To reduce these matrix effects, researchers should favor lifetime or ratiometric measures, perform on-chip co-calibration under physiologically relevant conditions, use organelle-targeted and self-referenced probes, and report a complete and transparent error analysis. Several recurrent pitfalls merit explicit control:

• Buffer-to-cell drift can decouple calibration from intracellular behavior (65, 66).

• NIR excitation can introduce photothermal bias; temperature rise should be quantified as a function of power density and duty cycle (63, 64).

• At high probe loading, concentration dependence via energy-transfer upconversion or cross-relaxation distorts ratiometric outputs (62).

• Organelle heterogeneity demands proper targeting and co-localization controls to ensure that signals originate from the intended compartment (65, 66).

• Morphological integrity of the sensing probes should be verified after intracellular incorporation, for instance by transmission electron microscopy imaging, to ensure that structural features such as core–shell architectures remain intact and do not influence photophysical readouts.

• Environmental cross-talk from hydration, pH, and ions should be decoupled using orthogonal controls such as D₂O substitution and ionophores (74, 75).

Table 1 summarizes key information that should be included in reports of Ln-based intracellular sensing technologies to promote transparency and reproducibility. These elements encompass details of material composition, optical instrumentation, calibration procedures, control experiments, and in-cell metrology as well as data accessibility and error analysis.

NIR-II imaging

The second NIR window (NIR-II; 1,000–1,700 nm) combines centimeter-scale penetration with sub-10 µm resolution because scattering and autofluorescence are largely reduced, yielding signal-to-noise ratios up to four times higher than visible or NIR-I imaging (83, 84). Non-ionizing, low-power excitation and even afterglow emitters further minimize photothermal and radiation risks (85). These attributes make NIR-II optics a powerful complement to radiological modalities.

Ln emitters are particularly well suited to NIR-II. Their sharp f–f lines and long lifetimes enable time-gated detection, while ladder-like energy levels permit color/brightness/lifetime multiplexing (26). Representative advances include:

• Lifetime-programmed nanoparticles using core–multishell energy relays that span three orders of magnitude in NIR-II lifetimes, enabling depth-independent, time-domain multiplexing and in vivo discrimination of breast cancer biomarkers (86).

• Chromium (Cr³⁺)-sensitized Na₃CrF₆ hosts that boost Er³⁺ (1,540 nm), Tm³⁺ (1,622 nm), Yb³⁺ (1,000 nm), and Nd³⁺ (1,060 nm) emissions up to ~370-fold, operable with low-power 655 nm lasers, white light-emitting diodes, or persistent luminescence for high-contrast tumor imaging (87).

• Thermosensing in NIR-II, where Er³⁺/Yb³⁺ co-doped probes produce dual 980/1,550-nm output for ~200-µm-resolution cerebrovascular thermography (61).

• 1,530-nm-driven upconversion via Yb-sublattice energy migration, opening deeper-penetrating excitation routes for super-resolution and encrypted photonics (88).

Translational progress mirrors these photophysical gains. PEGylated NaYbF₄:Er/Ce@NaYF₄ (~1,550 nm) enabled high-resolution, longitudinal NIR-II imaging of bone architecture and early inflammation, approaching micro-CT performance (89). DNA-programmed, in vivo self-assembling NaGdF₄:Nd nanoprobes improved tumor retention and margin delineation under 1,060-nm excitation (90). X-ray-charged persistent-luminescence NaY(Gd)F₄:Ln nanocrystals provided background-free emission for >72 h at 1,064–1,525 nm, supporting deep-tissue multiplexing and MRI/PET co-imaging (91). When Ln-doped nanoparticles are coated with Fe/Mn bimetal-doped ZIF-8, multifunctional theranostic platforms can be created for NIR-II imaging and synergistic photodynamic/chemodynamic therapy (92). Collectively, these strategies push NIR-II imaging toward clinically relevant penetration depth, enhanced contrast, and quantitative functional readouts, enabling visualization of previously inaccessible biological processes. In the near term, their clinical impact will most likely be in applications such as intraoperative imaging and targeted tumor delineation, where high sensitivity and low background are advantageous. However, issues including particle accumulation, potential long-term toxicity, and variability in biological environments continue to limit clinical translation, highlighting the need for further system-level optimization (93, 94). As such, its current advantages are most evident in preclinical imaging and specialized intraoperative applications rather than routine clinical diagnostics.

Applications in X-ray imaging

X-rays (0.01–10 nm) exhibit photoelectric, Compton, and Rayleigh interactions that produce fast electrons and lower-energy photons (95). X-ray bioimaging accordingly falls into three readout classes: (i) CT, which measures beam attenuation; (ii) scintillator imaging, which records visible light emitted by a converter (i.e., scintillator) under X-ray excitation; and (iii) X-ray luminescence imaging, which captures newly generated UV-to-NIR light. Ln nanoprobes map naturally onto these three categories (Figure 3) (96).

Figure 3

Lanthanide-based agents for CT and spectral photon-counting CT

Clinical CT is widely used for its cost-effectiveness, manipulable contrast, high spatial resolution, and deep penetration, but soft tissues often require contrast media because intrinsic attenuation differences are small (97). Iodinated and barium agents are standard, yet they can suffer from short circulation, a relatively low iodine K-edge of 33.2 keV (the threshold energy for strong X-ray absorption), and potential toxicity (98). High-Z Ln offer stronger attenuation and higher K-edges than iodine or barium, making them attractive agents for conventional CT and spectral photon-counting CT (SPCCT) (97, 99). Unlike conventional CT, SPCCT uses energy-resolving photon-counting detectors to distinguish photons by energy, enabling K-edge imaging and material decomposition. This capability enhances contrast, reduces noise and radiation dose, and allows multicontrast visualization, where Ln agents with distinct K-edges are particularly advantageous for molecular and quantitative imaging (100).

Ln nanoparticles combine physiological stability, surface functionalization, longer blood half-life, and targeting. For example, Yb-based NaYbF₄:Er nanoparticles showed higher efficacy than clinical iodinated agents and gold/platinum/bismuth/tantalum (Au/Pt/Bi/Ta) nanoparticles (101). More recently, ultrasmall Yb nanoparticles leveraged the Yb K-edge (~61.3 keV) for high-performance contrast in both CT and SPCCT and enabled in vivo hydrogel tracking (102). For blood-pool imaging, Er-containing polymeric assemblies (PEG114-PLA53-encapsulated) provided colloidally stable formulations at 100 mg mL^–1 Er and high-resolution vascular imaging (dose of 0.2 mL per mouse) (103). GdF₃ nanocrystals with a Gd K-edge of 50.2 keV within the SPCCT tube range (30–120 keV) served as a stable, high-payload angiographic agent (104). Collectively, these studies underscore the potential of Ln carriers for CT guidance and radiotherapy planning. Their most immediate applications may lie in spectral CT and image-guided interventions, where energy-resolved contrast can provide additional value. However, compared with established clinical agents, these systems still require validation in terms of safety, dose optimization, and large-scale reproducibility before routine clinical use.

Scintillators for X-ray detection

Scintillators are materials that convert high-energy radiation, such as X-rays, into visible or near-infrared light, forming the basis of modern medical and security imaging systems. An optimal scintillator should combine high X-ray absorption efficiency, a fast response, and strong, stable light emission to ensure high-resolution, low-dose imaging. Ln-based scintillators meet these requirements by pairing strong photoelectric absorption with sharp, tunable 4f/5d emissions. Solution-phase synthesis of NaREF₄ (RE = Gd, Lu, Y) cores and core–shell nanostructures has yielded low-cost, low-toxicity converters with high light yield and suppressed afterglow via engineered energy migration (e.g., Ce³⁺/Gd³⁺ networks). Compared with bulk screens, nanoscintillators offer higher brightness, lower scattering, and ultrathin, flexible-film compatibility, enabling low-dose, high-resolution imaging (105). Nanoscintillators can even support persistent imaging, where afterglow luminescence continues for a defined period after excitation, allowing signal acquisition without continuous X-ray exposure. This persistence reduces radiation dose while enabling real-time or time-lapse monitoring—an important advance for biological and clinical imaging applications (96).

Inorganic scintillators

Current strategies, such as core–shell engineering, interstitial doping, and controlled defect formation, program radioluminescence output, afterglow lifetimes, and multicolor/persistent emission properties for biomedical and industrial imaging applications (106). Tb:NaLuF₄@NaYF₄ nanoscintillators enabled long-lasting X-ray luminescence, with radiance persisting for over 30 days via Frenkel-trap storage. When embedded in flexible polydimethylsiloxane (PDMS) films, these materials achieved spatial resolutions of ≥20 line pairs (lp)/mm even on curved surfaces (107). Time-dependent multicolor afterglow was achieved through regioselective doping of Pr³⁺, Tb³⁺, Dy³⁺, or Sm³⁺ activators in core–shell fluoride nanoparticles, which enabled distinct decay kinetics in the core and shell. Interstitial Na⁺ ions further enhanced the afterglow intensity by promoting anion Frenkel defect and trap formation (108). A dual heterogeneous interface further boosted X-ray persistent luminescence >40-fold across Dy³⁺, Tb³⁺, Pr³⁺, Er³⁺, and Tm³⁺, enabling delayed high-resolution imaging and three-dimensional (3D) reconstructions (109).

Ethylenediaminetetraacetic acid-capped NaGdF₄:Ce/Tb nanoparticles combined a Gd³⁺ migration sublattice with Ce³⁺ electron capture to deliver high X-ray-excited output, minimal afterglow, and 18.6 lp/mm resolution with excellent transparency (110). Gd³⁺-sensitized YF₃:Tb³⁺ microparticles in flexible PDMS reached 16.8 lp/mm while retaining mechanical robustness (111). Beyond X-rays, europium(III) oxide (Eu₂O₃) and gadolinium(III) oxide (Gd₂O₃) can be directly excited by β/γ radionuclides, suggesting routes to nanoparticle-specific single-photon emission CT (112). Multiwavelength capability was recently extended using stochastic photoluminescence and compressed encoding with randomly arrayed lanthanide transducers for imaging across X-ray, UV, and NIR bands (113). In this system, lanthanide transducers act as wavelength-selective encoders whose stochastic emission patterns are computationally decoded to reconstruct simultaneous multiband images. The approach enables compact, high-throughput imaging from X-ray to NIR for applications in materials analysis, biomedical imaging, and remote sensing.

Organic/MOF scintillators

In addition to inorganic Ln scintillators, hybrid platforms that couple high-Z Ln (attenuators/emitters) with organic antennas, particularly MOFs and Ln complexes, enable designable energy-transfer pathways and X-ray-induced luminescence, broadening material choices for flexible, low-dose screens and molecular imaging (27).

MOFs are self-assembly molecular architectures formed by coordinating organic linkers to metal ions or clusters (114). Considering the rich luminescence of Ln, Eu/Tb isostructural MOFs have been engineered as X-ray scintillators. These scintillators have continuous color tuning from red to green via Eu³⁺/Tb³⁺ ratio control and radiation/humidity stability that surpasses widely used thallium-doped cesium iodide (CsI:Tl) scintillators, a conventional benchmark material for high-efficiency X-ray detection (115). Tb-cluster MOFs further enable linker-energy tuning of X-ray-induced emission, originating from the lanthanide center, the linker, or both (116). Heterometallic frameworks that integrate [Cu₄I₄] antennas with Ln emitters create dense, rigid networks that suppress non-radiative loss and funnel energy efficiently to the Ln (117). Beyond node design, Ln doping into otherwise non-luminescent MOFs, achieved through an “energy puzzle” match between the linker triplet state and the Ln excitation level, facilitates efficient energy transfer, boosting detection sensitivity >100-fold and enabling X-ray-induced NIR (700–1,200 nm) output beneficial for deep-tissue imaging (118). Together, using Ln as nodes or dopants provides a flexible toolkit to optimize MOF scintillators for radiation detection and bioimaging.

Lanthanide complexes as scintillators

Lanthanide–organic complexes provide a complementary route. Foundational work by Kukinov et al. showed that Ln complexes (Nd, Sm, Eu, Tb, Dy, Tm, and Er) exhibit distinct radioluminescence vs. photoluminescence behaviors and follow a dual-excitation mechanism: direct Ln excitation or ligand-mediated transfer from secondary photons generated by X-ray interactions (119). Building on this, Eu and Tb complexes containing 2,6-di(1H-pyrazol-1-yl)isonicotinate (bppCOO⁻) achieved high-sensitivity X-ray detection; Tb-bppCOO-2 reached sub-diagnostic dose limits and, embedded in PDMS, delivered 7 lp/mm imaging in flexible films (120). Extending this approach, a new class of ultrabright organic Ln scintillators has recently been developed by a near-unity triplet-exciton recycling mechanism. In this context, excitons refer to bound electron–hole pairs that mediate the transfer of excitation energy within the material (121). Under X-ray irradiation, the absorbed high-energy photons generate cascades of secondary electrons that thermalize to produce electron–hole pairs. The resulting excitonic energy is efficiently captured by the surrounding organic ligands and subsequently transferred back to the Ln centers. These designs produced >10³-fold higher radioluminescence than conventional organic phosphors, with color and lifetime tunability. They also showed promise for X-ray-mediated photodynamic therapy (PDT), which enables activation of photosensitizers within deep tissues for cancer treatment, overcoming the limited penetration of conventional light-based PDT. This illustrates how molecular-level control of triplet harvesting can drive flexible, low-dose, high-resolution X-ray-responsive systems.

X-ray-activated luminescence

X-ray luminescence arises from the radiative recombination of charge carriers generated by high-energy X-ray photons, yielding emission from the UV to NIR-II. Relative to UV–visible or NIR excitation, X-ray activation provides deeper tissue penetration, negligible autofluorescence, and high spatial resolution, enabling deep-tissue imaging with improved contrast (99, 106). Ln carriers are especially suited for both imaging and X-ray-activated therapies due to their high atomic numbers, rich 4f manifolds, and robust photophysics (27). Two modalities are commonly used: transient luminescence for real-time readout and persistent luminescence for post-irradiation tracking.

Transient luminescence

Fluoride hosts of the type ALnF₄ (A = alkali metal) support efficient X-ray downconversion through favorable transfer of self-trapped excitons to activators. Systematic investigations defined how host composition, structure, and surface chemistry govern Eu³⁺ emission and enabled hexagonal NaGdF₄:Eu³⁺ probes for in vivo imaging (122). Ln-doped NaYF₄ nanoprobes have produced stable NIR-II (~1,530 nm) emission under X-ray excitation for real-time tumor and lymphatic tracking (123). Extending beyond nanoparticles, nanoscale benzene-1,4-dicarboxylate-based MOFs doped with Eu³⁺/Tb³⁺ offer sharp, tunable, X-ray-excitable emission and customizable platforms for optical molecular imaging and theranostics (124).

Persistent luminescence

Persistent luminescence refers to the afterglow emission that persists after the cessation of excitation, owing to the gradual release of trapped carriers. It enables imaging without ongoing irradiation, lowering the total dose (125–127). Emission lifetimes reflect both intrinsic 4f configurations and extrinsic lattice/coordination effects (128). Strategies for exploiting persistent luminescence within imaging systems include trap engineering in core–shell fluoride nanoparticles for time-dependent multicolor afterglow (129), soft X-ray-rechargeable SrAl₂O₄:Eu²⁺ phosphors for repeated, deep-tissue imaging (~2.5 cm) with high signal-to-noise ratios (130), and surface-passivated NaYF₄:Ln³⁺@NaYF₄ systems (480–1,060 nm) that enable low-dose afterglow and multichannel optical information storage (131). NIR-II persistent emitters based on NaY(Gd)F₄ (Er³⁺/Nd³⁺/Ho³⁺/Tm³⁺) provide >72-h afterglow, improved signal-to-noise ratios, and tunable outputs via dopant and shell optimization (91). For sensing/dosimetry, an ingestible capsule integrating Ln-based persistent nanoscintillators with pH-responsive films and wireless readout enables in situ monitoring of dose, pH, and temperature in vivo (132). By enabling efficient X-ray-to-light conversion, these systems broaden imaging strategies from attenuation-based contrast to luminescence-based detection.

Applications in magnetic resonance imaging

MRI is one of the most powerful and widely used non-invasive diagnostic tools in medicine and biomedical research, offering exceptional soft tissue contrast and 3D anatomical detail without ionizing radiation. Its sensitivity to local magnetic environments also makes it valuable for tracking physiological and molecular processes in vivo. Ln ions, particularly Gd³⁺, have reshaped MRI by shortening the relaxation times of nearby water protons, thereby boosting signal intensity and anatomical resolution. Gadopentetate dimeglumine (Gd-DTPA; Magnevist, Bayer) and gadoterate meglumine (Gd-DOTA; Dotarem, Guerbet) chelates remain the clinical standard (12). However, current clinical agents face constraints such as modest relaxivity, short retention, and risks tied to kinetic/thermodynamic stability and toxicity (10, 11, 98). These limitations have motivated the development of next-generation systems with higher relaxivity, stronger kinetic stability, lower toxicity, and extended imaging windows (Figure 4). Inorganic Ln carriers (e.g., nanoparticles) and emerging biosynthetic carriers are promising research directions.

Figure 4

Chemical carriers

Gd-fluoride nanoparticles are prominent in MRI applications owing to their chemical versatility and strong relaxivity (5, 6, 11, 12). The imaging performance of these agents can be tuned via size, surface chemistry, and lattice composition (6).

Size/surface effects

Johnson et al. developed ultrasmall, size-tunable NaGdF₄ nanoparticles (2.5–8.0 nm) and showed that smaller particles deliver higher ionic relaxivity owing to greater surface-to-volume ratios. Surface Gd³⁺-dominated relaxivity and rotational correlation time further modulated contrast (28). Botta and co-workers tuned the citrate:Gd³⁺ ratio on GdF₃ to control stability, size, and water access. Relaxometry revealed that surface Gd³⁺ ions dominate relaxivity by tuning water interactions, with up to two coordinated water molecules per ion and a surface area-normalized relaxivity ~40 Mm^–1 s^–1 at 1.5 Tesla (T) (21). These studies demonstrate size control and surface engineering as levers to maximize T₁ performance.

Stimulus-responsive designs

Yi et al. created NaGdF₄–CaCO₃ nanoconjugates that act as pH-activated (“on–off”) T₁ probes (133). At physiological pH (~7.4), the calcium carbonate (CaCO₃) layer shields the ultrasmall NaGdF₄ particles from water, limiting inner-sphere water coordination to surface Gd³⁺ sites, so the probe is effectively “off” (low r₁ with minimal T₁ signal). In the mildly acidic tumor microenvironment (pH ~6.5–6.8), CaCO₃ dissolves, unmasking the ultrasmall NaGdF₄ core. This restores water access to surface Gd³⁺ ions, and combined with the high surface-to-volume ratio of ultrasmall particles (and favorable rotational dynamics), dramatically increases r₁, switching the probe “on”. This site-specific activation suppresses background signals in normal tissues and amplifies tumor contrast, delivering >60-fold enhancement compared with a clinical Gd chelate (e.g., Magnevist) under matched conditions.

Targeted, multimodal platforms

Luo et al. developed bioorthogonal lanthanide-doped nanoparticles for dual-modality tumor imaging that combine NIR-IIb fluorescence with T₁-weighted MRI (134). Targeting is achieved via copper-free click chemistry (strain-promoted azide-alkyne cycloaddition) to label azide-modified tumor cells, which sharply improves in vivo specificity. The probes use a multilayer core–shell architecture with a NaGdF₄ outer layer that provides strong T₁ contrast (r₁ = 7.56 mM^–1 s^–1). Relative to non-targeted controls, bioorthogonal labeling yielded a ~20-fold increase in NIR-IIb signal and a ~2-fold MRI enhancement at tumor sites, enabled high-resolution orthotopic brain tumor imaging, and maintained sustained contrast for up to 48 h, supporting precise, lower-dose cancer diagnostics. Beyond Gd³⁺, other Ln (e.g., Eu²⁺/Eu³⁺, Dy³⁺, and Tb³⁺) enable redox-responsive probes and efficient T₂ relaxation at high fields, supporting a shift toward responsive, targeted, and multimodal MRI platforms (135–137).

Biosynthetic carriers

Protein-based MRI contrast agents enable cell- and tissue-specific imaging with high biocompatibility and reduced systemic toxicity. Unlike small-molecule chelates, proteins can be genetically engineered to present targeting motifs, tune metal coordination and water access (thereby optimizing relaxivity), and respond to physiological cues, enabling dynamic, functional MRI and longer monitoring windows in vivo.

Early engineered scaffolds

Yang et al. introduced protein MRI agents by installing Gd³⁺-binding sites into the CD2 scaffold, achieving relaxivity up to 117 mM^–1 s^–1 at 1.5 T (well above Gd-DTPA) through optimized coordination geometry, higher hydration number, and damped internal motion (38). The constructs showed high Gd³⁺ selectivity, serum stability, prolonged circulation, and sustained T₁ contrast in mice. Building on this, a gastrin-releasing peptide (GRP)-targeted variant, upon binding to the GRP receptor (GRPR), selectively accumulated in GRPR-positive prostate tumors and produced durable T₁-weighted enhancement (138). PEGylation further boosted performance by conjugating PEG chains to the engineered protein ProCA1, increasing r₁ relaxivity by up to ~200%, prolonging blood half-life, enhancing solubility, and reducing immunogenicity (139).

ProCA32 series and disease-focused designs

Xue et al. evolved the platform to create the ProCA32 contrast agent, incorporating mutations that improved Gd³⁺ selectivity, relaxivity, and pharmacokinetics for liver cancer imaging. ProCA32 supports dual T₁/T₂ readouts with relaxivities up to ~10-fold higher than clinical agents, enabling detection of liver metastases as small as 0.24 mm (140). Subsequent disease-specific variants include ProCA32.CXCR4, which permits highly sensitive detection of liver micrometastases in uveal melanoma models down to 0.1 mm³ (40), and ProCA32.collagen1, which targets collagen to visualize early/late liver fibrosis and non-alcoholic steatohepatitis with robust dual-contrast imaging and sensitivity to fibrotic heterogeneity and vascular remodeling (39).

Lanmodulin-based agents

Expanding the protein toolbox, Liu et al. recently engineered a single-point mutation into lanmodulin, a natural Ln-binding protein (35, 141), yielding LanND with enhanced Gd³⁺ affinity and molecular relaxivity >50 mM^–1 s^–1 at 3 T. The compact LanND–Gd complex supported high-resolution brain vasculature imaging (~100 µm) and prolonged renal function monitoring, with efficient renal clearance, minimal toxicity, and strong biocompatibility.

In comparison with clinically approved Gd chelates, next-generation Ln systems can achieve substantially higher relaxivity, longer circulation time, and molecular targeting in the near term. However, these advantages are primarily demonstrated in preclinical models, as pharmacokinetics, safety profiles, and regulatory pathways are not yet well established. Further efforts are therefore needed to enable clinical translation.

Future directions

Ongoing refinement of Ln-based imaging and therapeutic platforms remains crucial for translating laboratory innovations into clinical practice. Future efforts should focus on improving biocompatibility, targeting precision, and achieving multimodal integration while leveraging progress in molecular design, computational modeling, and photophysical understanding.

Sustainability and potential transition-metal substitutes

Despite their frequent designation as “rare earth” elements, Ln are not geochemically rare: their average crustal abundance is ~125 ppm—higher than that of several other technologically important metals. However, their use is constrained by access difficulties due to the dispersal of ores and the need for concentrated refining. Recent computational studies mapping Ln solvation free-energy landscapes further underscore the complexity of refining and separation processes, highlighting the importance of understanding coordination dynamics to improve efficiency and sustainability (142). Reflecting this, the European Union lists rare earth elements as Critical Raw Materials and is advancing regulation to secure sustainable supply (143, 144). As an example, alkaline/carbonatitic rocks on Fuerteventura (Canary Islands) contain up to ~10,300 ppm total rare earths with enrichment in the heavy rare earths (Yb, Er, and Tm) (145), comparable to Bayan Obo in China and Mountain Pass in the United States. Mining and refining are costly and environmentally burdensome, and large-scale recycling technology remains immature. Against this backdrop, it is prudent to explore partial substitutes that reduce dependence on Ln³⁺ while preserving key optical windows.

A promising route is to deploy transition-metal ions that can deliver narrow, efficient emission in the red–NIR/short-wave infrared spectra, akin to 4f–4f bands. Viable examples include d³ (octahedral) ions such as Cr³⁺ and Mn⁴⁺, which exhibit sharp ²E→⁴A₂ lines in the ~620–700 nm range, and d² (tetrahedral) Mn⁵⁺ with an ¹E→³A₂ band at ~1,100–1,250 nm—transitions that are only weakly host-dependent and thus spectrally “line-like”. Additional candidates (e.g., selected Ni²⁺/Co²⁺ hosts) offer narrow features under the right ligand fields (146). Upconversion based on transition-metal centers, especially in halide hosts doped with second/third-row transition-metal ions, has also been demonstrated extensively by Güdel and co-workers (147, 148), providing a non-lanthanide path to anti-Stokes emission. That said, transition-metal ions bring trade-offs: stronger vibronic coupling and shorter lifetimes than those of Ln³⁺, greater sensitivity to crystal-field and phonon environments, and often tighter host-engineering windows to suppress non-radiative loss.

Multimodal imaging

The future of Ln-based imaging will pair multimodal contrast with intelligent analysis. In practice, clinical and preclinical settings often prioritize a single, reliable modality for simplicity and throughput, while multimodal constructs are most valuable during probe development and validation. When deployed, integrated agents that combine MRI, optical, and X-ray signals can co-register anatomy with molecular function, reducing redundant scans and improving diagnostic accuracy (149, 150). Beyond Ln, protein- or cell-based transducers merit exploration to complement modality-specific limitations (151, 152). Multimodal imaging has several advantages over single-modal imaging. A clear example of complementarity is MRI vs. optical imaging: MRI delivers depth-independent, high-resolution 3D anatomy but has sensitivity in the tens of micromolar range, whereas optical imaging offers high sensitivity, submicron spatial resolution, and real-time imaging, but limited tissue penetration. Dual optical imaging/MRI strategies therefore unite high anatomical accuracy with high sensitivity and subcellular resolution (153). Looking forward, key challenges include integrating multiple contrast mechanisms into a single biocompatible platform, achieving quantitative cross-modality correlation, and ensuring regulatory feasibility. Progress in nanostructure design, signal calibration, and data fusion algorithms is expected to further advance the translational potential of multimodal lanthanide systems.

AI/computation for materials and probe design

In parallel, the rise of AI and machine learning will play a central role in managing and interpreting complex imaging data (154). AI algorithms already assist in image reconstruction, noise reduction, tumor detection, brain metabolome analysis, and even predicting disease progression (155–157). They can also accelerate probe discovery by analyzing structure–activity relationships and simulating biological interactions (154). Recent studies further highlight the value of AI and machine learning in nanomaterial design: machine learning models can predict the stability and coordination chemistry of Ln–ligand complexes with high accuracy and assess biological responses to Ln-doped nanoparticles, such as cytotoxicity or reactive oxygen species generation (158, 159). Such data-driven insights enable rapid optimization of probe composition, brightness, and biocompatibility. As imaging shifts toward real-time and longitudinal monitoring, AI will enable adaptive imaging strategies tailored to individual patients. The combination of smart Ln probes with AI-powered data analytics holds great promise for advancing precision medicine, guiding therapeutic decisions, and improving patient outcomes in both research and clinical settings.

Overcoming translational hurdles

The translational progress of imaging agents rests on three pillars: biology, regulation, and manufacturing/access. Biologically, it is essential to clarify the long-term fate and clearance of the agent (i.e., its uptake by the reticuloendothelial system in the liver and spleen and its clearance by hepatobiliary vs. renal routes), quantify protein–corona effects and immunogenicity, and account for the in-cell vs. buffer calibration drift in sensors (123). Uncertainties in biodistribution, persistence, and potential long-term toxicity remain major concerns (94). Regulatorily, nanoparticle probes are evaluated as drugs or drug–device combinations and must meet good manufacturing practice/good laboratory practice requirements, demonstrate batch reproducibility, ensure sterilization/endotoxin control, and use validated analytics; for Gd systems, safety considerations favor macrocyclic chelates or protein scaffolds (11, 39, 40). The complexity of these systems also poses challenges for regulatory approval and comparison with established clinical agents. On manufacturing and access, a shortage of commercial suppliers for standardized Ln nanoprobes slows adoption. Preclinical units may test lab-made materials but ultimately prefer agents approved by the United States Food and Drug Administration and/or European Medicines Agency and often require benchmarking against approved contrast agents (e.g., dyes). Scaling will benefit from continuous-flow synthesis, robust ligand exchange, and shelf-stable, filter-sterilizable formulations (104). Cost, manufacturing complexity, and sustainable sourcing of Ln are additional considerations that may influence large-scale adoption. To enable comparability and review, reports should include absolute quantum yield (integrating sphere), power-dependent lifetimes, limit of detection/limit of quantification with confidence intervals, traceable temperature/force calibrations, relaxivity at the stated field/temperature, endotoxin levels, and hydrodynamic size/polydispersity index before and after protein exposure. At present, the lack of standardized evaluation criteria further hampers cross-study comparison and translation, underscoring the need for more coordinated efforts moving forward.

Conclusions

Ln-based carriers have greatly advanced biomedical imaging by offering high-resolution, sensitive, and multifunctional contrast across various imaging modalities. Their unique optical and magnetic properties, combined with tunable design and strong biocompatibility, have enabled breakthroughs in MRI, X-ray, and optical imaging. From nanoparticles to engineered proteins, these systems support targeted, long-lasting, and responsive imaging. Collectively, these developments not only improve imaging performance but also enable new ways to detect, quantify, and integrate biological information across scales. Although Ln systems offer clear advantages in multiplexing, sensitivity, and functional imaging, established clinical agents remain superior in standardization, safety validation, and scalability. Hence, further efforts are needed to address safety (e.g., long-term metabolism and clearance), scalability, and regulatory challenges of Ln systems before widespread clinical translation can be achieved. In the near term, Ln-based systems are most likely to impact applications requiring multiplexing, deep-tissue sensitivity, or functional imaging rather than broadly replacing established clinical probes.

In the future, the integration of Ln probes with emerging technologies, such as AI, multimodal data fusion, and intelligent delivery systems, will further enhance precision, adaptability, and translational potential. Advances in probe design, mechanistic understanding, and real-time image analysis are expected to bridge the gap between molecular imaging and personalized medicine. As the field moves toward dynamic, patient-tailored, and feedback-driven diagnostics, Ln-based platforms are expected to play an increasingly important role in shaping the next generation of intelligent biomedical imaging and theranostics.

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