Doping Lanthanide Ions in Colloidal Semiconductor Nanocrystals for Brighter Photoluminescence.

The spectrally narrow, long-lived luminescence of lanthanide ions makes optical nanomaterials based on these elements uniquely attractive from both a fundamental and applicative standpoint. A highly coveted class of such nanomaterials is represented by colloidal lanthanide-doped semiconductor nanocrystals (LnSNCs). Therein, upon proper design, the poor light absorption intrinsically featured by lanthanides is compensated by the semiconductor moiety, which harvests the optical energy and funnel it to the luminescent metal center. Although a great deal of experimental effort has been invested to produce efficient nanomaterials of that sort, relatively modest results have been obtained thus far. As of late, halide perovskite nanocrystals have surged as materials of choice for doping lanthanides, but they have non-negligible shortcomings in terms of chemical stability, toxicity, and light absorption range. The limited gamut of currently available colloidal LnSNCs is unfortunate, given the tremendous technological impact that these nanomaterials could have in fields like biomedicine and optoelectronics. In this review, we provide an overview of the field of colloidal LnSNCs, while distilling the lessons learnt in terms of material design. The result is a compendium of key aspects to consider when devising and synthesizing this class of nanomaterials, with a keen eye on the foreseeable technological scenarios where they are poised to become front runners.

Thermoresponsive Polymeric Nanolenses Magnify the Thermal Sensitivity of Single Upconverting Nanoparticles.

Lanthanide-based upconverting nanoparticles (UCNPs) are trustworthy workhorses in luminescent nanothermometry. The use of UCNPs-based nanothermometers has enabled the determination of the thermal properties of cell membranes and monitoring of in vivo thermal therapies in real time. However, UCNPs boast low thermal sensitivity and brightness, which, along with the difficulty in controlling individual UCNP remotely, make them less than ideal nanothermometers at the single-particle level. In this work, it is shown how these problems can be elegantly solved using a thermoresponsive polymeric coating. Upon decorating the surface of NaYF4 :Er3+ ,Yb3+ UCNPs with poly(N-isopropylacrylamide) (PNIPAM), a >10-fold enhancement in optical forces is observed, allowing stable trapping and manipulation of a single UCNP in the physiological temperature range (20-45 °C). This optical force improvement is accompanied by a significant enhancement of the thermal sensitivity- a maximum value of 8% °C+1 at 32 °C induced by the collapse of PNIPAM. Numerical simulations reveal that the enhancement in thermal sensitivity mainly stems from the high-refractive-index polymeric coating that behaves as a nanolens of high numerical aperture. The results in this work demonstrate how UCNP nanothermometers can be further improved by an adequate surface decoration and open a new avenue toward highly sensitive single-particle nanothermometry.

In Vivo Near-Infrared Imaging Using Ternary Selenide Semiconductor Nanoparticles with an Uncommon Crystal Structure.

The implementation of in vivo fluorescence imaging as a reliable diagnostic imaging modality at the clinical level is still far from reality. Plenty of work remains ahead to provide medical practitioners with solid proof of the potential advantages of this imaging technique. To do so, one of the key objectives is to better the optical performance of dedicated contrast agents, thus improving the resolution and penetration depth achievable. This direction is followed here and the use of a novel AgInSe2 nanoparticle-based contrast agent (nanocapsule) is reported for fluorescence imaging. The use of an Ag2 Se seeds-mediated synthesis method allows stabilizing an uncommon orthorhombic crystal structure, which endows the material with emission in the second biological window (1000-1400 nm), where deeper penetration in tissues is achieved. The nanocapsules, obtained via phospholipid-assisted encapsulation of the AgInSe2 nanoparticles, comply with the mandatory requisites for an imaging contrast agent-colloidal stability and negligible toxicity-and show superior brightness compared with widely used Ag2 S nanoparticles. Imaging experiments point to the great potential of the novel AgInSe2 -based nanocapsules for high-resolution, whole-body in vivo imaging. Their extended permanence time within blood vessels make them especially suitable for prolonged imaging of the cardiovascular system.

Asymmetric Ring Opening in a Tetrazine-Based Ligand Affords a Tetranuclear Opto-Magnetic Ytterbium Complex.

We report the formation of a tetranuclear lanthanide cluster, [Yb4 (bpzch)2 (fod)10 ] (1), which occurs from a serendipitous ring opening of the functionalised tetrazine bridging ligand, bpztz (3,6-dipyrazin-2-yl-1,2,4,5-tetrazine) upon reacting with Yb(fod)3 (fod- =6,6,7,7,8,8,8-heptafluoro-2,2-dimethyl-3,5-octandionate). Compound 1 was structurally elucidated via single-crystal X-ray crystallography and subsequently magnetically and spectroscopically characterised to analyse its magnetisation dynamics and its luminescence behaviour. Computational studies validate the observed MJ energy levels attained by spectroscopy and provides a clearer picture of the slow relaxation of the magnetisation dynamics and relaxation pathways. These studies demonstrate that 1 acts as a single-molecule magnet (SMM) under an applied magnetic field in which the relaxation occurs via a combination of Raman, direct, and quantum tunnelling processes, a behaviour further rationalised analysing the luminescent properties. This marks the first lanthanide-containing molecule that forms by means of an asymmetric tetrazine decomposition.

Spectral Shape Recovery and Analysis Via Data-driven Connections.

We introduce a novel learning-based method to recover shapes from their Laplacian spectra, based on establishing and exploring connections in a learned latent space. The core of our approach consists in a cycle-consistent module that maps between a learned latent space and sequences of eigenvalues. This module provides an efficient and effective link between the shape geometry, encoded in a latent vector, and its Laplacian spectrum. Our proposed data-driven approach replaces the need for ad-hoc regularizers required by prior methods, while providing more accurate results at a fraction of the computational cost. Moreover, these latent space connections enable novel applications for both analyzing and controlling the spectral properties of deformable shapes, especially in the context of a shape collection. Our learning model and the associated analysis apply without modifications across different dimensions (2D and 3D shapes alike), representations (meshes, contours and point clouds), nature of the latent space (generated by an auto-encoder or a parametric model), as well as across different shape classes, and admits arbitrary resolution of the input spectrum without affecting complexity. The increased flexibility allows us to address notoriously difficult tasks in 3D vision and geometry processing within a unified framework, including shape generation from spectrum, latent space exploration and analysis, mesh super-resolution, shape exploration, style transfer, spectrum estimation for point clouds, segmentation transfer and non-rigid shape matching. SUPPLEMENTARY INFORMATION: The online version supplementary material available at 10.1007/s11263-021-01492-6.

Shining New Light on Multifunctional Lanthanide Single-Molecule Magnets.

Single-molecule magnets (SMMs) are at the forefront of new technological advances in quantum information processing and spintronics. Despite the recent impressive breakthroughs in extending the magnetic blocking temperatures beyond liquid-nitrogen temperatures, significant challenges await in terms of integrating and addressing such compounds in devices. With this ultimate goal in mind, the design of multifunctional SMMs not only allows to imbue molecules of interest with specific properties that would allow for in situ monitoring of the SMM operation in real time, but can also provide critical insights into our understanding of the magnetic behaviour. In this Review, we highlight how magnetism and luminescence can be harmoniously combined within single molecules to achieve these objectives. The key design principles to attain the simultaneous combination of photoluminescence and slow relaxation of the magnetization are discussed, along with an outlook on how such molecules could be beneficial for emerging next-generation spintronics devices.

Triplet-State Position and Crystal-Field Tuning in Opto-Magnetic Lanthanide Complexes: Two Sides of the Same Coin.

Lanthanide-complex-based luminescence thermometry and single-molecule magnetism are two effervescent fields of research, owing to the great promise they hold from an application standpoint. The high thermal sensitivity achievable, their contactless nature, along with sub-micrometric spatial resolution make these luminescent thermometers appealing for accurate temperature probing in miniaturised electronics. To that end, single-molecule magnets (SMMs) are expected to revolutionise the field of spintronics, thanks to the improvements made in terms of their working temperature-now surpassing that of liquid nitrogen-and manipulation of their spin state. Hence, the combination of such opto-magnetic properties in a single molecule is desirable in the aim of overcoming, among others, addressability issues. Yet, improvements must be made through design strategies for the realisation of the aforementioned goal. Moving forward from these considerations, we present a thorough investigation of the effect that changes in the ligand scaffold of a family of terbium complexes have on their performance as luminescent thermometers and SMMs. In particular, an increased number of electron-withdrawing groups yields modifications of the metal coordination environment and a lowering of the triplet state of the ligands. These effects are tightly intertwined, thus, resulting in concomitant variations of the SMM and the luminescence thermometry behaviour of the complexes. Supported by ab initio calculations, we can rationally interpret the observed trends and provide solid foundations for the development of opto-magnetic lanthanide complexes.

Small and Bright Lithium-Based Upconverting Nanoparticles.

In the context of light-mediated tumor treatment, the application of ultraviolet (UV) radiation can initiate drug release and photodynamic therapy. However, its limited penetration depth in tissues impedes the subcutaneous applicability of such radiation. On the contrary, near-infrared (NIR) light is not energetic enough to initiate secondary photochemical processes, but can pierce tissues at a significantly greater depth. Upconverting nanoparticles (UCNPs) unify the advantages of both extremes of the optical spectrum, they can be excited by NIR irradiation and emit UV light through the process of upconversion, effective NIR-to-UV generation being attained with UCNPs as large as 100 nm. However, in anticipation of biomedical applications, the size of UCNPs must be greatly minimized to favor their cellular internalization; yet straightforward size reduction negatively affects the NIR-to-UV upconversion efficiency. Herein, we propose a two-step strategy to obtain small yet bright lithium-based UCNPs. First, we synthesized UCNPs as small as 5 nm by controlling the relative amount of coordinating ligands, namely oleylamine (OM) and oleic acid (OA). Although these UCNPs were chemically unstable, particle coarsening via an annealing process in the presence of fresh OA yielded structurally stable and highly monodisperse sub-10 nm crystals. Second, we grew a shell with controlled thickness on these stabilized cores of UCNPs, improving the NIR-to-UV upconversion by orders of magnitude. Particularly in the case of LiYbF4:Tm3+/LiYF4 UCNPs, their NIR-to-UV upconversion surpassed the gold standard 90 nm-sized LiYF4:Tm3+, Yb3+ UCNPs. All in all, these UCNPs show great potential within the biomedical framework as they successfully combine the requirements of small size, deep tissue NIR penetration and bright UV emission.

Highly Efficient Copper Sulfide-Based Near-Infrared Photothermal Agents: Exploring the Limits of Macroscopic Heat Conversion.

Among the foreseeable therapeutic approaches at the cellular level, nanoplatform-driven photothermal therapy is a thriving tool for the selective eradication of malignant tissues with minimal side effects to healthy ones. Hence, chemically versatile, near-infrared absorbing plasmonic nanoparticles are distinctly appealing and most sought after as efficient photothermal agents. In this work, a straightforward method to synthesize monodisperse PEGylated copper sulfide nanoparticles of pure covellite (CuS) phase, featuring strong localized surface plasmonic resonance absorption in the near-infrared and flexible surface chemistry, imparted by monomethyl ether polyethylene glycol molecules, is developed and optimized. These nanoparticles show a remarkable photothermal heat conversion efficiency (HCE) of 71.4%, which is among the highest for CuS systems and rivals that of plasmonic noble metal nanostructures. Moreover, through critical evaluation and mathematical modeling of the material's properties and measurement methodology, it is assessed that the calculated HCE values drastically depend on experimental conditions such as wavelength-dependent solvent absorption properties, sol concentration, and optical path. These findings are of paramount relevance to the photothermal community, since they call for a standardization of the procedure for the evaluation of the HCE of proposed photothermal agents, in order to make the reported values universally and reliably comparable.

Microwave-Assisted Solvothermal Synthesis of Upconverting and Downshifting Rare-Earth-Doped LiYF4 Microparticles.

Growing attention toward optically active materials has prompted the development of novel synthesis methods for a more reliable and efficient access to these systems. In this regard, microwave-assisted approaches provide unique advantages over traditional solvothermal methods reliant on convectional heating: namely, significantly shorter reaction durations, more rigid reaction conditions, and thus a higher degree of reproducibility. Reported herein for the first time is a rapid synthesis of rare-earth (RE3+)-doped LiYF4 upconverting and downshifting microparticles with well-defined bipyramidal morphology and good size dispersion via a microwave-assisted solvothermal process. The suggested material growth mechanism identifies a suitable Li+ to RE3+ ion ratio, an abundance of pH-sensitive acetate surface-capping ligands, and an appropriate reaction temperature/time profile as crucial for enabling a phase transformation of an intermediary yttrium ammonium fluoride phase into LiYF4 and subsequent particle ripening. The versatility of the reported method is highlighted by its extension toward the synthesis of other state of the art M(RE)F4 (M = alkali metal) optical materials: RE3+-doped LiYbF4 microparticles and ß-NaGdF4 and α-NaYF4 nanoparticles. All of the obtained Yb3+/Er3+- and Yb3+/Tm3+-codoped M(RE)F4 materials exhibited characteristic upconversion emission, while downshifting capabilities were induced through Ce3+/Tb3+ codoping of LiYF4. Further attention was devoted to single-particle optical characterization via hyperspectral imaging of Yb3+/Er3+- and Yb3+/Tm3+-codoped LiYF4 microparticles to explore the spatial variability of upconversion emission within individual particles.

Early in vivo detection of denervation-induced atrophy by luminescence transient nanothermometry.

Denervation induces skeletal muscle atrophy due to the loss of control and feedback with the nervous system. Unfortunately, muscle atrophy only becomes evident days after the denervation event when it could be irreversible. Alternative diagnosis tools for early detection of denervation-induced muscle atrophy are, thus, required. In this work, we demonstrate how the combination of transient thermometry, a technique already used for early diagnosis of tumors, and infrared-emitting nanothermometers makes possible the in vivo detection of the onset of muscle atrophy at short (<1 day) times after a denervation event. The physiological reasons behind these experimental results have been explored by performing three dimensional numerical simulations based on the Pennes' bioheat equation. It is concluded that the alterations in muscle thermal dynamics at the onset of muscle atrophy are consequence of the skin perfusion increment caused by the alteration of peripheral nervous autonomous system. This work demonstrates the potential of infrared luminescence thermometry for early detection of diseases of the nervous system opening the venue toward the development of new diagnosis tools.

Synergistic Enhancement of Photodynamic Cancer Therapy with Mesenchymal Stem Cells and Theranostic Nanoparticles.

Nanoparticles engineered to combat cancer and other life-threatening diseases may significantly improve patient outcomes. However, inefficient nanoparticle delivery to tumors limits their use and necessitates the development of complex delivery approaches. Here, we examine this issue by harnessing the tumor-homing abilities of human mesenchymal stem cells (MSCs) to deliver a decoupled theranostic complex of rare earth-doped nanoparticles (dNPs) and photosensitizer chlorin e6 (Ce6) to tumors. We show that both bone-marrow- and skin-derived MSCs can transport the dNP-Ce6 complex inside tumor spheroids, which is challenging to accomplish by passive delivery alone. MSCs deliver the dNP-Ce6 complex across the tumor spheroid, facilitating more effective photodynamic damage and tumor destruction than passively accumulated dNP-Ce6. The dNP-Ce6 complex also provides the built-in ability to monitor the MSC migration without causing undesired phototoxicity, which is essential for maximal and side-effect-free delivery of nanoparticles. Our results demonstrate how MSCs can be used as delivery vehicles for the transportation of the dNP-Ce6 complex, addressing the limitations of passive nanoparticle delivery and providing light-based theranostics.

New Insights in Luminescence and Quenching Mechanisms of Ag2S Nanocrystals through Temperature-Dependent Spectroscopy.

Bright near-infrared-emitting Ag2S nanocrystals (NCs) are used for in vivo temperature sensing relying on a reversible variation in intensity and photoluminescence lifetime within the physiological temperature range. Here, to gain insights into the luminescence and quenching mechanisms, we investigated the temperature-dependent luminescence of Ag2S NCs from 300 to 10 K. Interestingly, both emission and lifetime measurements reveal similar and strong thermal quenching from 200 to 300 K, indicating an intrinsic quenching process that limits the photoluminescence quantum yield at room temperature, even for perfectly passivated NCs. The low thermal quenching temperature, broadband emission, and multiexponential microsecond decay behavior suggest the optical transition involves strong lattice relaxation, which is consistent with the recombination of a Ag+-trapped hole with a delocalized conduction band electron. Our findings offer valuable insights for understanding the optical properties of Ag2S NCs and the thermal quenching mechanism underlying their temperature-sensing capabilities.

Neural Networks Push the Limits of Luminescence Lifetime Nanosensing.

Luminescence lifetime-based sensing is ideally suited to monitor biological systems due to its minimal invasiveness and remote working principle. Yet, its applicability is limited in conditions of low signal-to-noise ratio (SNR) induced by, e.g., short exposure times and presence of opaque tissues. Herein this limitation is overcome by applying a U-shaped convolutional neural network (U-NET) to improve luminescence lifetime estimation under conditions of extremely low SNR. Specifically, the prowess of the U-NET is showcased in the context of luminescence lifetime thermometry, achieving more precise thermal readouts using Ag2 S nanothermometers. Compared to traditional analysis methods of decay curve fitting and integration, the U-NET can extract average lifetimes more precisely and consistently regardless of the SNR value. The improvement achieved in the sensing performance using the U-NET is demonstrated with two experiments characterized by extreme measurement conditions: thermal monitoring of free-falling droplets, and monitoring of thermal transients in suspended droplets through an opaque medium. These results broaden the applicability of luminescence lifetime-based sensing in fields including in vivo experimentation and microfluidics, while, hopefully, spurring further research on the implementation of machine learning (ML) in luminescence sensing.

Spotlight on Luminescence Thermometry: Basics, Challenges, and Cutting-Edge Applications.

Luminescence (nano)thermometry is a remote sensing technique that relies on the temperature dependency of the luminescence features (e.g., bandshape, peak energy or intensity, and excited state lifetimes and risetimes) of a phosphor to measure temperature. This technique provides precise thermal readouts with superior spatial resolution in short acquisition times. Although luminescence thermometry is just starting to become a more mature subject, it exhibits enormous potential in several areas, e.g., optoelectronics, photonics, micro- and nanofluidics, and nanomedicine. This work reviews the latest trends in the field, including the establishment of a comprehensive theoretical background and standardized practices. The reliability, repeatability, and reproducibility of the technique are also discussed, along with the use of multiparametric analysis and artificial-intelligence algorithms to enhance thermal readouts. In addition, examples are provided to underscore the challenges that luminescence thermometry faces, alongside the need for a continuous search and design of new materials, experimental techniques, and analysis procedures to improve the competitiveness, accessibility, and popularity of the technology.

Ion-induced bias in Ag2S luminescent nanothermometers.

Luminescence nanothermometry allows measuring temperature remotely and in a minimally invasive way by using the luminescence signal provided by nanosized materials. This technology has allowed, for example, the determination of intracellular temperature and in vivo monitoring of thermal processes in animal models. However, in the biomedical context, this sensing technology is crippled by the presence of bias (cross-sensitivity) that reduces the reliability of the thermal readout. Bias occurs when the impact of environmental conditions different from temperature also modifies the luminescence of the nanothermometers. Several sources that cause loss of reliability have been identified, mostly related to spectral distortions due to interaction between photons and biological tissues. In this work, we unveil an unexpected source of bias induced by metal ions. Specifically, we demonstrate that the reliability of Ag2S nanothermometers is compromised during the monitoring of photothermal processes produced by iron oxide nanoparticles. The observed bias occurs due to the heat-induced release of iron ions, which interact with the surface of the Ag2S nanothermometers, enhancing their emission. The results herein reported raise a warning to the community working on luminescence nanothermometry, since they reveal that the possible sources of bias in complex biological environments, rich in molecules and ions, are more numerous than previously expected.

3D Optical Coherence Thermometry Using Polymeric Nanogels.

In nanothermometry, the use of nanoparticles as thermal probes enables remote and minimally invasive sensing. In the biomedical context, nanothermometry has emerged as a powerful tool where traditional approaches, like infrared thermal sensing and contact thermometers, fall short. Despite the strides of this technology in preclinical settings, nanothermometry is not mature enough to be translated to the bedside. This is due to two major hurdles: the inability to perform 3D thermal imaging and the requirement for tools that are readily available in the clinics. This work simultaneously overcomes both limitations by proposing the technology of optical coherence thermometry (OCTh). This is achieved by combining thermoresponsive polymeric nanogels and optical coherence tomography (OCT)-a 3D imaging technology routinely used in clinical practice. The volume phase transition of the thermoresponsive nanogels causes marked changes in their refractive index, making them temperature-sensitive OCT contrast agents. The ability of OCTh to provide 3D thermal images is demonstrated in tissue phantoms subjected to photothermal processes, and its reliability is corroborated by comparing experimental results with numerical simulations. The results included in this work set credible foundations for the implementation of nanothermometry in the form of OCTh in clinical practice.

Exploring the Origin of the Thermal Sensitivity of Near-Infrared-II Emitting Rare Earth Nanoparticles.

Rare-earth doped nanoparticles (RENPs) are attracting increasing interest in materials science due to their optical, magnetic, and chemical properties. RENPs can emit and absorb radiation in the second biological window (NIR-II, 1000-1400 nm) making them ideal optical probes for photoluminescence (PL) in vivo imaging. Their narrow emission bands and long PL lifetimes enable autofluorescence-free multiplexed imaging. Furthermore, the strong temperature dependence of the PL properties of some of these RENPs makes remote thermal imaging possible. This is the case of neodymium and ytterbium co-doped NPs that have been used as thermal reporters for in vivo diagnosis of, for instance, inflammatory processes. However, the lack of knowledge about how the chemical composition and architecture of these NPs influence their thermal sensitivity impedes further optimization. To shed light on this, we have systematically studied their emission intensity, PL decay time curves, absolute PL quantum yield, and thermal sensitivity as a function of the core chemical composition and size, active-shell, and outer-inert-shell thicknesses. The results revealed the crucial contribution of each of these factors in optimizing the NP thermal sensitivity. An optimal active shell thickness of around 2 nm and an outer inert shell of 3.5 nm maximize the PL lifetime and the thermal response of the NPs due to the competition between the temperature-dependent back energy transfer, the surface quenching effects, and the confinement of active ions in a thin layer. These findings pave the way for a rational design of RENPs with optimal thermal sensitivity.

Less is more: dimensionality reduction as a general strategy for more precise luminescence thermometry.

Thermal resolution (also referred to as temperature uncertainty) establishes the minimum discernible temperature change sensed by luminescent thermometers and is a key figure of merit to rank them. Much has been done to minimize its value via probe optimization and correction of readout artifacts, but little effort was put into a better exploitation of calibration datasets. In this context, this work aims at providing a new perspective on the definition of luminescence-based thermometric parameters using dimensionality reduction techniques that emerged in the last years. The application of linear (Principal Component Analysis) and non-linear (t-distributed Stochastic Neighbor Embedding) transformations to the calibration datasets obtained from rare-earth nanoparticles and semiconductor nanocrystals resulted in an improvement in thermal resolution compared to the more classical intensity-based and ratiometric approaches. This, in turn, enabled precise monitoring of temperature changes smaller than 0.1 °C. The methods here presented allow choosing superior thermometric parameters compared to the more classical ones, pushing the performance of luminescent thermometers close to the experimentally achievable limits.

New opportunities for light-based tumor treatment with an "iron fist".

The efficacy of photodynamic treatments of tumors can be significantly improved by using a new generation of nanoparticles that take advantage of the unique properties of the tumor microenvironment.