Upconverting Nanoparticles Coated with Light-Breakable Mesoporous Silica for NIR-Triggered Release of Hydrophobic Molecules.

Upconverting nanoparticles (UCNPs) doped with Yb3+ and Tm3+ are near-infrared (NIR) to ultraviolet (UV) transducers that can be used for NIR-controlled drug delivery. However, due to the low quantum yield of upconversion, high laser powers and long irradiation times are required to trigger this drug release. In this work, we report the one-step synthesis of a nanocomposite consisting of a LiYbF4:Tm3+@LiYF4 UCNP coated with mesoporous UV-breakable organosilica shells of various thicknesses. We demonstrate that a thin shell accelerates the breakage of the shell at 1 W/cm2 NIR light exposure, a laser power up to 9 times lower than that of conventional systems. When the mesopores are loaded with hydrophobic vitamin D3 precursor 7-dehydrocholesterol (7-DH), shell breakage results in subsequent cargo release. Its minimal toxicity in HeLa cells and successful internalization into the cell cytoplasm demonstrate its biocompatibility and potential application in biological systems. The tunability of this system due to its simple, one-step synthesis process and its ability to operate at low laser powers opens up avenues in UCNP-powered NIR-triggered drug delivery toward a more scalable, flexible, and ultimately translational option.

Short-wave Infrared Photoluminescence Lifetime Mapping of Rare-Earth Doped Nanoparticles Using All-Optical Streak Imaging.

The short-wave infrared (SWIR) photoluminescence lifetimes of rare-earth doped nanoparticles (RENPs) have found diverse applications in fundamental and applied research. Despite dazzling progress in the novel design and synthesis of RENPs with attractive optical properties, existing optical systems for SWIR photoluminescence lifetime imaging are still considerably restricted by inefficient photon detection, limited imaging speed, and low sensitivity. To overcome these challenges, SWIR photoluminescence lifetime imaging microscopy using an all-optical streak camera (PLIMASC) is developed. Synergizing scanning optics and a high-sensitivity InGaAs CMOS camera, SWIR-PLIMASC has a 1D imaging speed of up to 138.9 kHz in the spectral range of 900-1700 nm, which quantifies the photoluminescence lifetime of RENPs in a single shot. A 2D photoluminescence lifetime map can be acquired by 1D scanning of the sample. To showcase the power of SWIR-PLIMASC, a series of core-shell RENPs with distinct SWIR photoluminescence lifetimes is synthesized. In particular, using Er3+ -doped RENPs, SWIR-PLIMASC enables multiplexed anti-counterfeiting. Leveraging Ho3+ -doped RENPs as temperature indicators, this system is applied to SWIR photoluminescence lifetime-based thermometry. Opening up a new avenue for efficient SWIR photoluminescence lifetime mapping, this work is envisaged to contribute to advanced materials characterization, information science, and biomedicine.

The Coming of Age of Neodymium: Redefining Its Role in Rare Earth Doped Nanoparticles.

Among luminescent nanostructures actively investigated in the last couple of decades, rare earth (RE3+) doped nanoparticles (RENPs) are some of the most reported family of materials. The development of RENPs in the biomedical framework is quickly making its transition to the ∼800 nm excitation pathway, beneficial for both in vitro and in vivo applications to eliminate heating and facilitate higher penetration in tissues. Therefore, reports and investigations on RENPs containing the neodymium ion (Nd3+) greatly increased in number as the focus on ∼800 nm radiation absorbing Nd3+ ion gained traction. In this review, we cover the basics behind the RE3+ luminescence, the most successful Nd3+-RENP architectures, and highlight application areas. Nd3+-RENPs, particularly Nd3+-sensitized RENPs, have been scrutinized by considering the division between their upconversion and downshifting emissions. Aside from their distinctive optical properties, significant attention is paid to the diverse applications of Nd3+-RENPs, notwithstanding the pitfalls that are still to be addressed. Overall, we aim to provide a comprehensive overview on Nd3+-RENPs, discussing their developmental and applicative successes as well as challenges. We also assess future research pathways and foreseeable obstacles ahead, in a field, which we believe will continue witnessing an effervescent progress in the years to come.

Decoupled Rare-Earth Nanoparticles for On-Demand Upconversion Photodynamic Therapy and High-Contrast Near Infrared Imaging in NIR IIb.

Rare-earth doped multi-shell nanoparticles slated for theranostic applications produce a variety of emission bands upon near-infrared (NIR) excitation. Their downshifting emission is useful for high-contrast NIR imaging, while the upconversion light can induce photodynamic therapy (PDT). Unfortunately, integration of imaging and therapy is challenging. These modalities are better to be controlled independently so that, with the help of imaging, selective delivery of a theranostic agent at the site of interest could be ensured prior to on-demand PDT initiation. We introduce here multi-shell rare-earth doped nanoparticles (RENPs) arranged in a manner to produce only downshifting emission for NIR imaging when excited at one NIR wavelength and upconversion emission for therapeutic action by using a different excitation wavelength. In this work, multi-shell RENPs with a surface-bound sensitizer have been synthesized for decoupled 1550 nm downshifting emission upon 800 nm excitation and 550 nm upconversion emission caused by 980 nm irradiation. The independently controlled emission bands allow for high-contrast NIR imaging in NIR-IIb of optical transparency that gives high-contrast images due to significantly reduced light scattering. This can be conducted prior to PDT using 980 nm to produce upconverted light at 550 nm that excites the RENP surface-bound photosensitizer, Rose Bengal (RB), to effect photodynamic therapy with high specificity and safer theranostics.

Cubic versus hexagonal - phase, size and morphology effects on the photoluminescence quantum yield of NaGdF4:Er3+/Yb3+ upconverting nanoparticles.

Upconverting nanoparticles (UCNPs) are well-known for their capacity to convert near-infrared light into UV/visible light, benefitting various applications where light triggering is required. At the nanoscale, loss of luminescence intensity is observed and thus, a decrease in photoluminescence quantum yield (PLQY), usually ascribed to surface quenching. We evaluate this by measuring the PLQY of NaGdF4:Er3+,Yb3+ UCNPs as a function of size (ca. 15 to 100 nm) and shape (spheres, cubes, hexagons). Our results show that the PLQY of α-phase NaGdF4 Er3+,Yb3+ surpasses that of ß-NaGdF4 for sizes below 20 nm, an observation related to distortion of the crystal lattice when the UCNPs become smaller. The present study also underlines that particle shape must not be neglected as a relevant parameter for PLQY. In fact, based on a mathematical nucleus/hull volumetric model, shape was found to be particularly relevant in the 20 to 60 nm size range of the investigated UCNPs.

Polymer brush coated upconverting nanoparticles with improved colloidal stability and cellular labeling.

Upconverting nanoparticles (UCNPs) possess great potential for biomedical application. UCNPs absorb and convert near-infrared (NIR) radiation in the biological imaging window to visible (Vis) and even ultraviolet (UV) radiation. NIR excitation offers reduced scattering and diminished autofluorescence in biological samples, whereas the emitted UV-Vis and NIR photons can be used for cancer treatment and imaging, respectively. However, UCNPs are usually synthesized in organic solvents and are not readily suitable for biomedical application due to the hydrophobic nature of their surface. Herein, we have removed the hydrophobic ligands from the synthesized UCNPs and coated the bare UCNPs with two custom-made hydrophilic polyelectrolytes (synthesized via the reversible addition-fragmentation chain transfer (RAFT) polymerization method). Polymers containing different amounts of PEGylated and carboxylic groups were studied. Coating with both polymers increased the upconversion (UC) emission intensity and photoluminescence lifetime values of the UCNPs, which directly translates to more efficient cancer cell labeling nanoprobes. The polymer composition plays a crucial role in the modification of UCNPs, not only with respect to their colloidal stability, but also with respect to the cellular uptake. Colloidally unstable bare UCNPs aggregate in cell culture media and precipitate, rendering themselves unsuitable for any biomedical use. However, stabilization with polymers prevents UCNPs from aggregation, increases their uptake in cells, and improves the quality of cellular labeling. This investigation sheds light on the appropriate coating for UCNPs and provides relevant insights for the rational development of imaging and therapeutic tools.

Fast wide-field upconversion luminescence lifetime thermometry enabled by single-shot compressed ultrahigh-speed imaging.

Photoluminescence lifetime imaging of upconverting nanoparticles is increasingly featured in recent progress in optical thermometry. Despite remarkable advances in photoluminescent temperature indicators, existing optical instruments lack the ability of wide-field photoluminescence lifetime imaging in real time, thus falling short in dynamic temperature mapping. Here, we report video-rate upconversion temperature sensing in wide field using single-shot photoluminescence lifetime imaging thermometry (SPLIT). Developed from a compressed-sensing ultrahigh-speed imaging paradigm, SPLIT first records wide-field luminescence intensity decay compressively in two views in a single exposure. Then, an algorithm, built upon the plug-and-play alternating direction method of multipliers, is used to reconstruct the video, from which the extracted lifetime distribution is converted to a temperature map. Using the core/shell NaGdF4:Er3+,Yb3+/NaGdF4 upconverting nanoparticles as the lifetime-based temperature indicators, we apply SPLIT in longitudinal wide-field temperature monitoring beneath a thin scattering medium. SPLIT also enables video-rate temperature mapping of a moving biological sample at single-cell resolution.

Uptake of Upconverting Nanoparticles by Breast Cancer Cells: Surface Coating versus the Protein Corona.

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-, SiO2-, and phospholipid micelle-coated RENPs (LiYF4:Yb3+,Tm3+). 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 SiO2-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.

Autofluorescence-Free In Vivo Imaging Using Polymer-Stabilized Nd3+-Doped YAG Nanocrystals.

Neodymium-doped yttrium aluminum garnet (YAG:Nd3+) has been widely developed during roughly the past 60 years and has been an outstanding fluorescent material. It has been considered as the gold standard among multipurpose solid-state lasers. Yet, the successful downsizing of this system into the nanoregimen has been elusive, so far. Indeed, the synthesis of a garnet structure at the nanoscale, with enough crystalline quality for optical applications, was found to be quite challenging. Here, we present an improved solvothermal synthesis method producing YAG:Nd3+ nanocrystals of remarkably good structural quality. Adequate surface functionalization using asymmetric double-hydrophilic block copolymers, constituted of a metal-binding block and a neutral water-soluble block, provides stabilized YAG:Nd3+ nanocrystals with long-term colloidal stability in aqueous suspensions. These newly stabilized nanoprobes offer spectroscopic quality (long lifetimes, narrow emission lines, and large Stokes shifts) close to that of bulk YAG:Nd3+. The narrow emission lines of YAG:Nd3+ nanocrystals are exploited by differential infrared fluorescence imaging, thus achieving an autofluorescence-free in vivo readout. In addition, nanothermometry measurements, based on the ratiometric fluorescence of the stabilized YAG:Nd3+ nanocrystals, are demonstrated. The progress here reported paves the way for the implementation of this new stabilized YAG:Nd3+ system in the preclinical arena.

Inert Shell Effect on the Quantum Yield of Neodymium-Doped Near-Infrared Nanoparticles: The Necessary Shield in an Aqueous Dispersion.

Lanthanide-doped nanoparticles (LnNPs) are versatile near-infrared (NIR) emitting nanoprobes that have led to their growing interest for use in biomedicine-related imaging. Toward the brightest LnNPs, high photoluminescence quantum yield (PLQY) values are attained by implementing core/shell engineering, particularly with an optically inert shell. In this work, a thorough investigation is performed to quantify how an outer inert shell maintains the PLQY of Nd3+-doped LnNPs dispersed in an aqueous environment. Three relevant quantitative findings affecting the PLQY of Nd3+-doped LnNPs are identified: (i) the PLQY of core LnNPs is improved 3-fold upon inert shell coating; (ii) PLQY decreases with increasing Nd3+ doping despite the inert shell; and (iii) solvent quenching has a major influence on the PLQY of the LnNPs, though it is relatively lessened for high Nd3+ doping. Overall, we shed new light on the impact of the LnNP architecture on the NIR emission, as well as on the quenching effects caused by doping concentration and solvent molecules.

Spectral characterization of LiYbF4 upconverting nanoparticles.

In light of the recent developments on Yb3+-based upconverting rare-earth nanoparticles (RENPs), we have systematically explored the spectral features of LiYbF4:RE3+/LiYF4 core/shell RENPs doped with various amounts of Tm3+, Er3+, or Ho3+. Tm3+-RENPs displayed photoluminescence from the UV to near-infrared (NIR), and the dominant high-photon-order upconversion emission of these RENPs was tunable by Tm3+ doping. Similarly, Er3+- and Ho3+-RENPs with green and red upconversion showed wide color tuning, depending on the doping amount and excitation power density. From steady-state power plot and photoluminescence decay studies we have observed respective changes in upconversion photon order and average lifetime that attest to a number of cross-relaxation processes occurring at higher RE3+ doping concentration. Particularly in the case of Tm3+-RENPs, cross-relaxation promotes four- and five-photon order upconversion emission in the UV and blue spectral regions. The quantum yield of high-order upconversion emission was on par with classic Yb3+/Tm3+-doped systems, yet due to the high number of sensitizer ions in the LiYbF4 host these RENPs are expected to be brighter and thus better suited for applications such as controlled drug delivery or optogenetics. Overall, LiYbF4:RE3+/LiYF4 RENPs are promising systems to effectively generate high-order upconversion emissions, owing to excitation energy confinement within the Yb3+ network and its efficient funneling to the activator dopants.

Effect of light scattering on upconversion photoluminescence quantum yield in microscale-to-nanoscale materials.

Scattering affects excitation power density, penetration depth and upconversion emission self-absorption, resulting in particle size -dependent modifications of the external photoluminescence quantum yield (ePLQY) and net emission. Micron-size NaYF4:Yb3+, Er3+ encapsulated phosphors (∼4.2 µm) showed ePLQY enhancements of >402%, with particle-media refractive index disparity (Δn): 0.4969, and net emission increases of >70%. In sub-micron phosphor encapsulants (∼406 nm), self-absorption limited ePLQY and emission as particle concentration increases, while appearing negligible in nanoparticle dispersions (∼31.8 nm). These dependencies are important for standardising PLQY measurements and optimising UC devices, since the encapsulant can drastically enhance UC emission.

Terahertz three-dimensional monitoring of nanoparticle-assisted laser tissue soldering.

In view of minimally-invasive clinical interventions, laser tissue soldering assisted by plasmonic nanoparticles is emerging as an appealing concept in surgical medicine, holding the promise of surgeries without sutures. Rigorous monitoring of the plasmonically-heated solder and the underlying tissue is crucial for optimizing the soldering bonding strength and minimizing the photothermal damage. To this end, we propose a non-invasive, non-contact, and non-ionizing modality for monitoring nanoparticle-assisted laser-tissue interaction and visualizing the localized photothermal damage, by taking advantage of the unique sensitivity of terahertz radiation to the hydration level of biological tissue. We demonstrate that terahertz radiation can be employed as a versatile tool to reveal the thermally-affected evolution in tissue, and to quantitatively characterize the photothermal damage induced by nanoparticle-assisted laser tissue soldering in three dimensions. Our approach can be easily extended and applied across a broad range of clinical applications involving laser-tissue interaction, such as laser ablation and photothermal therapies.

Influence of halide ions on the structure and properties of copper indium sulphide quantum dots.

In the synthesis of CuInS2 quantum dots (QDs), the halide ions present in the copper salts influence the QD growth and optical properties. X-ray absorption spectroscopy allowed rationalizing the halide incorporation in the lattice and the dependence of electronic properties of the material on the ion's polarizability and interaction with hydrophobic moieties.

Surface vs. core N/S/Se-heteroatom doping of carbon nanodots produces divergent yet consistent optical responses to reactive oxygen species.

Carbon nanodots (CNDs) have attracted substantial scientific curiosity because of their intriguing stimuli-responsive optical properties. However, one obstacle to the more widespread use of CNDs as transducers for e.g., biodetection systems is incomplete knowledge regarding the underlying chemical changes responsible for this responsiveness, and how these chemical features can be engineered via the precursors chosen for CND synthesis. This study demonstrates that the precursor's functional groups play a key role in directing N/S/Se heteroatom dopants either towards the surface of the CNDs, towards the aromatic core, or towards small organic fluorophores in the core. Divergent optical properties, which were consistent amongst groups of CNDs prepared with similar precursors, were obtained including either a decrease or increase of fluorescence intensity in the presence of hydrogen peroxide. Moreover, CNDs were identified with orthogonal responsiveness to radical (hydroxyl radicals, ˙OH; down to 2.5 µM) vs. non-radical oxidants (H2O2; down to 50 µM), which suggests that control of the chemistry of CNDs via the choice of precursor could yield probes that are specific to certain sub-species of reactive oxygen species or entirely different molecules altogether, based on the way they chemically-modify the surface (respond faster) and core functional groups (respond slower) associated with chromophores/fluorophores of which the CNDs are composed.

Electrospun Upconverting Nanofibrous Hybrids with Smart NIR-Light-Controlled Drug Release for Wound Dressing.

Chronic wounds present a high risk of infection due to delayed and incomplete healing, leading to increased health risks and financial burden to health-care systems. Numerous approaches to promote wound healing have been extensively explored, especially the development of effective wound dressing materials embedded with therapeutic drug molecules. Despite advances made in this area, a remaining challenge to be addressed is the controlled, on-demand release of therapeutic molecules using noncytotoxic stimulus, for example, near-infrared (NIR) excitation. Here, we report a platform that allows for the development of electrospun poly(vinyl alcohol) (PVA) fibrous hybrids embedded with upconverting nanoparticles (UCNPs) and UV-cleavable levofloxacin conjugates for wound dressings. Upon irradiation with NIR light, the excited UCNPs emit UV light around 365 nm, which can cleave the o-nitrobenzyl (ONB) linkage of the levofloxacin conjugates in the PVA fiber, leading to controlled drug release. The release was observed to be triggered only under NIR and UV irradiation, with no effect in the dark. Furthermore, the antibacterial effect against Escherichia coli and Staphylococcus aureus was successfully demonstrated, highlighting the versatility of the electrospun upconverting fiber platform. The development of antibacterial fibrous meshes with on-demand release of encapsulated drugs is imperative for precise treatment of wound infections.

Nd3+ doped Gd3Sc2Al3O12 nanoparticles: towards efficient nanoprobes for temperature sensing.

Development of contactless temperature-probing nanoplatforms based on thermosensitive near-infrared (NIR) light-emitting nanoparticles opens up new horizons for biomedical theranostics at a deep tissue level. Here, we report on the crystallinity and relative thermal sensitivity of NIR emitting Nd3+ doped Gd3Sc2Al3O12 (GSAG:Nd3+) nanoparticles synthesized by a solvothermal method. The obtained nanoparticles are well-crystallized, with sizes less than 100 nm, and can be dispersed in water without any additional functionalization. Upon excitation at 806 nm, the nanoparticles exhibit emission in the first and second biological optical transparency windows. The temperature sensing properties were evaluated from the luminescence intensity ratio of the thermally coupled emission lines corresponding to the R1, R2→Z5 transitions between the Stark sublevels of the 4F3/2 and 4I9/2 electronic states of Nd3+ in the physiological temperature range of 20-50 °C. GSAG:Nd3+ nanoparticles exhibit a maximal relative thermal sensitivity of 0.20% °C-1, higher than that of YAG:Nd3+ nanoparticles used as a control, due to the difference in the crystal field of the host matrices. A higher synthesis temperature in the range of 300-400 °C was also provided to improve the crystallinity of the GSAG:Nd3+ nanoparticles which results in a higher relative thermal sensitivity. Our results demonstrate the potential of GSAG:Nd3+ nanoparticles as luminescence nanothermometers and emphasize the interest of the GSAG matrix itself, which with the presence of Gd, could lead to multimodal diagnostic applications in nanothermometry and magnetic resonance imaging (MRI).

Single-shot compressed optical-streaking ultra-high-speed photography.

Single-shot ultra-high-speed imaging is of great significance to capture transient phenomena in physics, biology, and chemistry in real time. Existing techniques, however, have a restricted application scope, a low sequence depth, or a limited pixel count. To overcome these limitations, we developed single-shot compressed optical-streaking ultra-high-speed photography (COSUP) with an imaging speed of 1.5 million frames per second, a sequence depth of 500 frames, and an (x,y) pixel count of 0.5 megapixels per frame. COSUP's single-shot ultra-high-speed imaging ability was demonstrated by recording single laser pulses illuminating through transmissive targets and by tracing a fast-moving object. As a universal imaging platform, COSUP is capable of increasing imaging speeds of a wide range of CCD and complementary metal-oxide-semiconductor cameras by four orders of magnitude. We envision COSUP to be applied in widespread applications in biomedicine and materials science.

Multifunctional Self-Assembled Supernanoparticles for Deep-Tissue Bimodal Imaging and Amplified Dual-Mode Heating Treatment.

Developing multifunctional therapeutic and diagnostic (theranostic) nanoplatforms is critical for addressing challenging issues associated with cancers. Here, self-assembled supernanoparticles consisting of superparamagnetic Fe3O4 nanoparticles and photoluminescent PbS/CdS quantum dots whose emission lies within the second biological window (II-BW) are developed. The proposed self-assembled Fe3O4 and PbS/CdS (II-BW) supernanoparticles [SASNs (II-BW)] exhibit outstanding photoluminescence detectable through a tissue as thick as 14 mm, by overcoming severe light extinction and concomitant autofluorescence in II-BW, and significantly enhanced T2 relaxivity (282 mM-1 s-1, ca. 4 times higher than free Fe3O4 nanoparticles) due to largely enhanced magnetic field inhomogeneity. On the other hand, SASNs (II-BW) possess the dual capacity to act as both magnetothermal and photothermal agents, overcoming the main drawbacks of each type of heating separately. When SASNs (II-BW) are exposed to the dual-mode (magnetothermal and photothermal) heating, the thermal energy transfer efficiency is amplified 7-fold compared with magnetic heating alone. These results, in hand with the excellent photo- and colloidal stability, and negligible cytotoxicity, demonstrate the potential use of SASNs (II-BW) for deep-tissue bimodal (magnetic resonance and photoluminescence) in vivo imaging, while simultaneously providing the possibility of SASNs (II-BW)-mediated amplified dual-mode heating treatment for cancer therapy.

Engineering efficient upconverting nanothermometers using Eu3+ ions.

Upconversion nanothermometry combines the possibility of optically sensing temperatures in very small areas, such as microfluidic channels or on microelectronic chips, with a simple detection setup in the visible spectral range and reduced heat transfer after near-infrared (NIR) excitation. We propose a ratiometric strategy based on Eu3+ ion luminescence activated through upconversion processes. Yb3+ ions act as a sensitizer in the NIR region (980 nm), and energy is transferred to Tm3+ ions that in turn excite Eu3+ ions whose luminescence is shown to be thermally sensitive. Tridoped SrF2:Yb3+,Tm3+,Eu3+ nanoparticles (average size of 17 nm) show a relative thermal sensitivity of 1.1% K-1 at 25.0 °C, in the range of the best ones reported to date for Ln3+-based nanothermometers based on upconversion emission. The present nanoparticle design allows us to exploit upconversion of lanthanide ions that otherwise cannot be directly excited upon NIR excitation and that may provide operational wavelengths with a highly stable read out to fill the spectral gaps currently existing in upconversion-based nanothermometry.