Lanthanide-based probes: beyond conventional imaging agents

observation. As Liu et al. summarize, these systems have been used for neuronal transport analysis, mechanosensing, intracellular thermometry, hydration-related sensing, and second near-infrared (NIR-II) imaging. These examples show that lanthanide carriers can move imaging beyond "where something is" toward "what is happening locally."This transition from location 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. show that their biomedical potential also extends to X-ray (computed tomography; CT) imaging and magnetic resonance imaging (MRI). In X-rayrelated imaging, high atomic numbers and X-ray-responsive luminescence make lanthanidecontaining materials attractive for CT, scintillator imaging, persistent luminescence, and low- However, multimodality should not be pursued simply for 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 lanthanidebased 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 Author 1 et al. Short title/running header 6 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 it 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. Lanthanidebinding 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 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, 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 wellcharacterized 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.