Lanthanide-based probes: beyond conventional imaging agents

Key points

• Lanthanide carriers are reshaping biomedical imaging by integrating optical, X-ray, and magnetic resonance functions within tunable material platforms.
• Their narrow emission bands, long lifetimes, photostability, and magnetic properties enable long-term tracking, deep-tissue imaging, and functional biological readouts.
• Future progress should move beyond brighter probes toward quantitatively reliable, biologically safe, and clinically translatable imaging systems.

In their lead article, Liu et al. (1) discuss a timely and important topic in biomedical imaging: lanthanide-based carriers. The article makes a clear case that lanthanide-based carriers are no longer niche luminescent materials used only in optical imaging. Instead, they are becoming versatile platforms that connect materials chemistry, photophysics, magnetic resonance, X-ray imaging, and biological sensing.

One of the strengths of this lead article is that it does not treat lanthanides simply as brighter alternatives to conventional probes. Rather, it emphasizes that their value comes from a distinctive combination of photophysical and magnetic properties. The shielded 4f orbitals of lanthanide ions generate narrow emission bands, long excited-state lifetimes, high photostability, and, in some cases, strong paramagnetism (2). These properties are especially useful for time-gated imaging, multiplexed detection, long-term tracking, and magnetic resonance contrast (3). In this respect, lanthanide carriers are not only signal sources. They are materials systems whose optical or magnetic output can be tuned through ion selection, host lattice design, coordination environment design, or surface engineering.

This point is particularly evident in upconversion nanoparticle-based imaging. Conventional fluorescent probes, including organic dyes and fluorescent proteins, have greatly advanced biological imaging, but they often suffer from photobleaching, blinking, shallow penetration, and background autofluorescence. Lanthanide-doped upconversion nanoparticles address several of these limitations by converting near-infrared excitation into higher-energy emissions (4). This optical process enables imaging under conditions that are difficult for conventional probes, especially in long-term tracking and deep-tissue observation. As Liu et al. summarize, these systems have been used for neuronal transport analysis, mechanosensing, intracellular thermometry, hydration-related sensing, and imaging in the second near-infrared window (NIR-II) (1). These examples show that lanthanide carriers can move imaging beyond “where something is” toward “what is happening locally”.

This transition from anatomical imaging to functional imaging may be one of the most important messages of the article. Biomedical imaging has traditionally relied heavily on anatomical contrast, lesion localization, and static morphological information. Lanthanide probes allow the reading of dynamic biological information because their emission intensity, lifetime, spectral ratio, and magnetic behavior can respond to local environmental changes (5). For example, luminescent thermometry can report local temperature variations, while hydration-sensitive probes can indicate changes in water accessibility near the particle surface. These functions are valuable because many biological processes, including tumor progression, inflammation, neuronal transport, and membrane-channel activity, are spatially heterogeneous and temporally dynamic. A probe that can report these changes in situ may provide information that is inaccessible to conventional endpoint assays.

The lead article benefits from its broad discussion of imaging modalities. Lanthanide carriers are often discussed mainly in optical imaging, especially upconversion and NIR-II luminescence. However, Liu et al. highlight recent research discoveries which show that their biomedical potential also extends to X-ray imaging, including computed tomography (CT), and magnetic resonance imaging (MRI) (1). In X-ray imaging, high atomic numbers and X-ray-responsive luminescence make lanthanide-containing materials attractive for CT, scintillator imaging, persistent luminescence, and low-dose diagnostics. In MRI, lanthanide chelates are already clinically relevant, while newer nanoparticles and lanthanide-binding proteins may improve relaxivity, targeting, stability, and safety. This multimodal potential is important because different imaging techniques provide different kinds of information. Optical imaging can offer high sensitivity and real-time readout, whereas CT and MRI provide a deeper anatomical context and whole-tissue localization (6).

However, multimodality should not be pursued simply for the sake of complexity. In preclinical studies, it is tempting to integrate fluorescence, CT, MRI, therapy, targeting, and sensing functions into a single nanoplatform. Yet a more complicated probe is not automatically a better probe. For clinical translation, every added function increases the demands on synthesis, reproducibility, toxicological evaluation, and regulatory approval. The most useful lanthanide carriers will likely be those in which each modality provides distinct and necessary information. A rational multimodal probe should answer a biological or clinical question more clearly than any single modality alone. Therefore, future studies should focus less on the number of functions integrated into one material and more on whether the combined readouts genuinely improve diagnosis, monitoring, or treatment guidance.

Quantitative reliability is another issue that deserves greater attention. Many lanthanide-based probes perform well in buffers or simplified model systems, but biological environments are far more complex. Local pH, viscosity, hydration, ionic strength, protein adsorption, and particle aggregation can all influence optical or magnetic readouts (7). For example, a probe designed for temperature sensing may also respond to hydration changes or local refractive index. A ratiometric sensor may be affected by probe concentration, surface modification, or energy-transfer interactions. These complications do not weaken the importance of lanthanide imaging, but they do mean that stronger validation standards are needed. In situ calibration, orthogonal controls, complete error analysis, and transparent reporting of imaging conditions should become routine in this field.

Clinical translation remains the central challenge. Liu et al. (1) appropriately note that many lanthanide systems are still at the proof-of-concept stage. This situation is understandable because nanomaterial-based imaging agents often face barriers related to biodistribution, clearance, long-term retention, batch reproducibility, immune interactions, and manufacturing scale-up. For lanthanide carriers, these issues are particularly important because free metal ions may raise safety concerns if the carrier is unstable (8). Therefore, future work should not only optimize brightness, lifetime, or imaging resolution but also examine carrier integrity, degradation pathways, excretion, and long-term biocompatibility. A strong imaging signal in a preclinical model is important but is not sufficient for translation. The probe must also be stable, reproducible, biologically safe, and capable of providing information that changes a biomedical decision.

In this context, biomolecular lanthanide carriers are especially interesting. Lanthanide-binding proteins and related biological scaffolds offer genetically programmable structures, defined coordination sites, and potential targeting ability. Compared with many inorganic nanoparticles, these systems may provide improved biological compatibility and more predictable molecular design. They also illustrate a broader point: lanthanide imaging does not rely only on small-molecule chelates or inorganic nanocrystals. It can also be advanced through biomolecular engineering. Of course, protein-based carriers have their own limitations, including immunogenicity, production complexity, and in vivo stability. Even so, they represent an important direction for developing more biologically integrated lanthanide imaging agents.

Artificial intelligence (AI) may further accelerate this field. Lanthanide signals are often multidimensional, involving wavelength, lifetime, intensity ratio, spatial distribution, and temporal evolution. AI-based methods could improve image reconstruction, denoising, spectral unmixing, lifetime analysis, and probe discovery (9). However, AI should be viewed as a tool for improving reliability and not as a replacement for physical understanding. Models trained on poorly calibrated or biased imaging data may produce apparently convincing but misleading results. The most useful AI-assisted strategies will be those built on well-characterized probe behavior, transparent datasets, and experimentally validated predictions.

In sum, lanthanide carriers are redefining biomedical imaging because they can deliver more than bright contrast. They can integrate optical, X-ray, and magnetic functions and may provide dynamic biological information across multiple length and time scales. The field should now move beyond demonstrating that lanthanide probes can image biological systems. It should ask which biological questions these probes answer better than existing technologies, which clinical problems they can realistically address, and what validation standards are needed to make their signals trustworthy. These questions encapsulate both the challenge and the opportunity for lanthanide-based biomedical imaging.

Generative AI statement

The authors declared that generative AI was not used in the creation of this manuscript.

Publisher’s note

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Footnotes

Edited and reviewed by: Ana de Bettencourt-Dias, University of Nevada, Reno, United States