Theranostic nanoagents targeted for personalized medicine provide a unified platform for therapeutics and diagnostics. To be able to discretely control each individually, allows for safer, more precise, and truly multifunctional theranostics. Rare earth doped nanoparticles can be rationally tailored to best match this condition with the aid of core/shell engineering. In such nanoparticles, the light‐mediated theranostic approach is functionally decoupled—therapeutics or diagnostics are prompted on‐demand, by wavelength‐specific excitation. These decoupled rare earth nanoparticles (dNPs) operate entirely under near‐infrared (NIR) excitation, for minimized light interference with the target and extended tissue depth action. Under heating‐free 806 nm irradiation, dNPs behave solely as high‐contrast NIR‐to‐NIR optical markers and nanothermometers, visualizing and probing the area of interest without prompting the therapeutic effect beforehand. On the contrary, 980 nm NIR irradiation is upconverted by the dNPs to UV/visible light, which triggers secondary photochemical processes, e.g., generation of reactive oxygen species by photosensitizers coupled to the dNPs, causing damage to cancer cells. Additionally, integration of NIR nanothermometry helps to control the temperature in the vicinity of the dNPs avoiding possible overheating and quenching of upconversion (UC) emission, harnessed for photodynamic therapy. Overall, a new direction is outlined in the development of state‐of‐the‐art rare earth based theranostic nanoplatforms.

The uptake and distribution of negatively charged superparamagnetic iron oxide (Fe3O4) nanoparticles (SPIONs) in mouse embryonic fibroblasts NIH3T3, and magnetic resonance imaging (MRI) signal influenced by SPIONs injected into experimental animals, were visualized and investigated. Cellular uptake and distribution of the SPIONs in NIH3T3 after staining with Prussian Blue were investigated by a bright-field microscope equipped with digital color camera. SPIONs were localized in vesicles, mostly placed near the nucleus. Toxicity of SPION nanoparticles tested with cell viability assay (XTT) was estimated. The viability of NIH3T3 cells remains approximately 95% within 3–24 h of incubation, and only a slight decrease of viability was observed after 48 h of incubation. MRI studies on Wistar rats using a clinical 1.5 T MRI scanner were showing that SPIONs give a negative contrast in the MRI. The dynamic MRI measurements of the SPION clearance from the injection site shows that SPIONs slowly disappear from injection sites and only a low concentration of nanoparticles was completely eliminated within three weeks. No functionalized SPIONs accumulate in cells by endocytic mechanism, none accumulate in the nucleus, and none are toxic at a desirable concentration. Therefore, they could be used as a dual imaging agent: as contrast agents for MRI and for traditional optical biopsy by using Prussian Blue staining.

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In recent years, photoluminescent gold nanoclusters have attracted considerable interest in both fundamental biomedical research and practical applications. Due to their ultrasmall size, unique molecule-like optical properties, and facile synthesis gold nanoclusters have been considered very promising photoluminescent agents for biosensing, bioimaging, and targeted therapy. Yet, interaction of such ultra-small nanoclusters with cells and other biological objects remains poorly understood. Therefore, the assessment of the biocompatibility and potential toxicity of gold nanoclusters is of major importance before their clinical application. In this study, the cellular uptake, cytotoxicity, and intracellular generation of reactive oxygen species (ROS) of bovine serum albumin-encapsulated (BSA-Au NCs) and 2-(N-morpholino) ethanesulfonic acid (MES)-capped photoluminescent gold nanoclusters (Au-MES NCs) were investigated. The results showed that BSA-Au NCs accumulate in cells in a similar manner as BSA alone, indicating an endocytotic uptake mechanism while ultrasmall Au-MES NCs were distributed homogeneously throughout the whole cell volume including cell nucleus. The cytotoxicity of BSA-Au NCs was negligible, demonstrating good biocompatibility of such BSA-protected Au NCs. In contrast, possibly due to ultrasmall size and thin coating layer, Au-MES NCs exhibited exposure time-dependent high cytotoxicity and higher reactivity which led to highly increased generation of reactive oxygen species. The results demonstrate the importance of the coating layer to biocompatibility and toxicity of ultrasmall photoluminescent gold nanoclusters.

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The ever-growing demand for fast, cheap, and reliable diagnostic tools for personalised medicine is encouraging scientists to improve existing technology platforms and to create new methods for the detection and quantification of biomarkers of clinical significance. Simultaneous detection of multiple analytes allows more accurate assessment of changes in biomarker expression and offers the possibility of disease diagnosis at the earliest stages. The concept of multiplexing, where multiple analytes can be detected in a single sample, can be tackled using several types of nanomaterial-based biosensors. Quantum dots are widely used photoluminescent nanoparticles and represent one of the most frequent choices for different multiplex systems. However, nanoparticles that incorporate gold, silver, and rare earth metals with their unique optical properties are an emerging perspective in the multiplexing field. In this review, we summarise progress in various nanoparticle applications for multiplexed biomarkers.

Fluorophores with multifunctional properties known as rare-earth-doped nanoparticles (RENPs) are promising candidates for bioimaging, therapy, and drug delivery. When applied in vivo , these nanoparticles (NPs) have to retain long blood-circulation time, bypass elimination by phagocytic cells, and successfully arrive at the target area. Usually, NPs in a biological medium are exposed to proteins, which form the so-called “protein corona” (PC) around the NPs and influence their targeted delivery and accumulation in cells and tissues. Different surface coatings change the PC size and composition, subsequently deciding the fate of the NPs. Thus, detailed studies on the PC are of utmost importance to determine the most suitable NP surface modification for biomedical use. When it comes to RENPs, these studies are particularly scarce. Here, we investigate the PC composition and its impact on the cellular uptake of citrate-, SiO 2 -, and phospholipid micelle-coated RENPs (LiYF 4 :Yb 3+ ,Tm 3+ ). We observed that the PC of citrate- and phospholipid-coated RENPs is relatively stable and similar in the adsorbed protein composition, while the PC of SiO 2 -coated RENPs is larger and highly dynamic. Moreover, biocompatibility, accumulation, and cytotoxicity of various RENPs in cancer cells have been evaluated. On the basis of the cellular imaging, supported by the inhibition studies, it was revealed that RENPs are internalized by endocytosis and that specific endocytic routes are PC composition dependent. Overall, these results are essential to fill the gaps in the fundamental understanding of the nano-biointeractions of RENPs, pertinent for their envisioned application in biomedicine.

Upconverting nanoparticles (UCNPs) are promising, new imaging probes capable of serving as multimodal contrast agents. In this study, monodisperse and ultrasmall core and core–shell UCNPs were synthesized via a thermal decomposition method. Furthermore, it was shown that the epitaxial growth of a NaGdF4 optical inert layer covering the NaGdF4:Yb,Er core effectively minimizes surface quenching due to the spatial isolation of the core from the surroundings. The mean diameter of the synthesized core and core–shell nanoparticles was ≈8 and ≈16 nm, respectively. Hydrophobic UCNPs were converted into hydrophilic ones using a nonionic surfactant Tween 80. The successful coating of the UCNPs by Tween 80 has been confirmed by Fourier transform infrared (FTIR) spectroscopy. Scanning electron microscopy (SEM), powder X-ray diffraction (XRD), photoluminescence (PL) spectra and magnetic resonance (MR) T1 relaxation measurements were used to characterize the size, crystal structure, optical and magnetic properties of the core and core–shell nanoparticles. Moreover, Tween 80-coated core–shell nanoparticles presented enhanced optical and MR signal intensity, good colloidal stability, low cytotoxicity and nonspecific internalization into two different breast cancer cell lines, which indicates that these nanoparticles could be applied as an efficient, dual-modal contrast probe for in vivo bioimaging.