Semiphysical Design Concept for Developing Miniaturized Microrobots In Vivo.

The miniaturization of biomedical microrobots is crucial for their in vivo applications. However, it is challenging to reduce their size while maintaining their biomedical functions. To resolve this contradiction, we propose a semiphysical design concept for developing miniaturized microrobots, in which invisible components such as light beams are utilized to replace most of the physical parts of a microrobot, thus minimizing its physical size without sacrificing its biomedical functions. According to this design, we have constructed a semiphysical microrobot (SPM) composed of main light beam, light-responsive microparticle, and auxiliary light beam, serving as the actuation system, recognition part, and surgical claws, respectively. Based on the functions of actuation, biosensing, and microsurgery, a SPM has been applied for a series of applications, including thrombus elimination at the branch vessel, stratified removal of multilayer thrombus, and biosensing-guided microsurgery. The proposed semiphysical design concept should bring new insight into the development of miniaturized biomedical microrobots.

Postoperatively Noninvasive Optogenetic Stimulation via Upconversion Nanoparticles Enhancing Sciatic Nerve Repair.

The efficacy of electrical stimulation facilitating peripheral nerve regeneration is evidenced extensively, while the associated secondary damage resulting from repeated electrode invasion and indiscriminate stimulation is inevitable. Here, we present an optogenetics strategy that utilizes upconversion nanoparticles (UCNPs) to convert deeply penetrating near-infrared excitation into blue emission, which activates an adeno-associated virus-encoding ChR2 photoresponsive ion channel on cell membranes. The induced Ca2+ flux, similar to the ion flux in the electrical stimulation approach, efficiently regulates viability and proliferation, secretion of nerve growth factor, and neural function of RSC96 cells. Furthermore, deep near-infrared excitation is harnessed to stimulate autologous Schwann cells in situ via a UCNP-composited scaffold, which enhances nerve sprouting and myelination, consequently promoting functional recovery, electrophysiological restoration, and reinnervation of damaged nerves. This developed postoperatively noninvasive optogenetics strategy presents a novel, minimally traumatic, and enduring therapeutic stimulus to effectively promote peripheral nerve repair.

Upconversion Nanoparticles Based Sensing: From Design to Point-of-Care Testing.

Rare earth-doped upconversion nanoparticles (UCNPs) have achieved a wide range of applications in the sensing field due to their unique anti-Stokes luminescence property, minimized background interference, excellent biocompatibility, and stable physicochemical properties. However, UCNPs-based sensing platforms still face several challenges, including inherent limitations from UCNPs such as low quantum yields and narrow absorption cross-sections, as well as constraints related to energy transfer efficiencies in sensing systems. Therefore, the construction of high-performance UCNPs-based sensing platforms is an important cornerstone for conducting relevant research. This work begins by providing a brief overview of the upconversion luminescence mechanism in UCNPs. Subsequently, it offers a comprehensive summary of the sensors' types, design principles, and optimized design strategies for UCNPs sensing platforms. More cost-effective and promising point-of-care testing applications implemented based on UCNPs sensing systems are also summarized. Finally, this work addresses the future challenges and prospects for UCNPs-based sensing platforms.

Construction of UCNPs-aptamer-AuNPs luminescence energy transfer probe for ratio detection of Staphylococcus aureus.

A ratio luminescence probe was developed for detecting Staphylococcus aureus (S. aureus) based on luminescence energy transfer (LET) using double-wavelength emission (550 nm and 812 nm) upconversion nanoparticles (UCNPs) as donor, gold nanoparticles (AuNPs) as acceptor and the aptamer for S. aureus as the specific recognition and link unit. The LET process could cause luminescence quenching because of the spectral overlap between the acceptor and the donor at 550 nm. In the presence of S. aureus, S. aureus selectively combined with the aptamer, and the AuNPs left the surface of UCNPs, which weakened the quenching effect and restored the luminescence of UCNPs. Based on this, the ratio detection was realized by monitoring the change of the luminescence signal of the probe at 550 nm and taking the luminescence signal at 812 nm as the reference signal. Crucially, the probe has a fast reaction speed, with a reaction time of 25 min, and the detection of S. aureus is realized in the concentration range of 5.0 × 103-3.0 × 105 CFU/ml, with the detection limit of 106 CFU/ml. Therefore, the ratio probe has great potential for detecting of S. aureus in food because of its high sensitivity, fast speed and good selectivity.

T790M mutation upconversion fluorescence biosensor via mild ATRP strategy and site-specific DNA cleavage of restriction endonuclease.

A unique combination of a specific nucleic acid restriction endonuclease (REase) and atom transfer radical polymerization (ATRP) signal amplification strategy was employed for the detection of T790M mutations prevalent in the adjuvant diagnosis of lung cancer. REase selectively recognizes and cleaves T790M mutation sites on double-stranded DNA formed by hybridization of a capture sequence and a target sequence. At the same time, the ATRP strategy resulted in the massive aggregation of upconverted nanoparticles (UCNPs), which significantly improved the sensitivity of the biosensor. In addition, the UCNPs have excellent optical properties and can eliminate the interference of autofluorescence in the samples, thus further improving the detection sensitivity. The proposed upconversion fluorescent biosensor is characterized by high specificity, high sensitivity, mild reaction conditions, fast response time, and a detection limit as low as 0.14 fM. The performance of the proposed biosensor is comparable to that of clinical PCR methods when applied to clinical samples. This work presents a new perspective for assisted diagnosis in the pre-intervention stage of tumor diagnostics in the early stage of precision oncology treatments.

Tumor-associated antigen-specific cell imaging based on upconversion luminescence and nucleic acid rolling circle amplification.

Tumor-associated antigen (TAA)-based diagnosis has gained prominence for early tumor screening, treatment monitoring, prognostic assessment, and minimal residual disease detection. However, limitations such as low sensitivity and difficulty in extracting non-specific binding membrane proteins still exist in traditional detection methods. Upconversion luminescence (UCL) exhibits unique physical and chemical properties under wavelength near-infrared light excitation. Rolling circle amplification (RCA) is an efficient DNA amplification technique with amplification factors as high as 105. Therefore, the above two excellent techniques can be employed for highly accurate imaging analysis of tumor cells. Herein, we developed a novel nanoplatform for TAA-specific cell imaging based on UCL and RCA technology. An aptamer-primer complex selectively binds to Mucin 1 (MUC1), one of TAA on cell surface, to trigger RCA reaction, generating a large number of repetitive sequences. These sequences provide lots of binding sites for complementary signal probes, producing UCL from lanthanide-doped upconversion nanoparticles (UCNPs) after releasing quencher group. The experimental results demonstrate the specific attachment of upconversion nanomaterials to cancer cells which express a high level of MUC1, indicating the potential of UCNPs and RCA in tumor imaging.

Engineering an upconversion fluorescence sensing platform with "off-on" pattern through specific DNAzyme-mediated signal amplification for supersensitive detection of uranyl ion.

An upconversion fluorescence sensing platform was developed with upconversion nanoparticles (UCNPs) as energy donors and gold nanoparticles (AuNPs) as energy acceptors, based on the FRET principle. They were used for quantitative detection of uranyl ions (UO22+) by amplifying the signal of the hybrid chain reaction (HCR). When UO22+ are introduced, the FRET between AuNPs and UCNPs can be modulated through a HCR in the presence of high concentrations of sodium chloride. This platform provides exceptional sensitivity, with a detection limit as low as 68 pM for UO22+ recognition. We have successfully validated the reliability of this method by analyzing authentic water samples, achieving satisfactory recoveries (89.00%-112.50%) that are comparable to those of ICP-MS. These results indicate that the developed sensing platform has the capability to identify trace UO22+ in complex environmental samples.

Upconversion-Powered Photoelectrochemical Bioanalysis for DNA Sensing.

In this work, we report a new concept of upconversion-powered photoelectrochemical (PEC) bioanalysis. The proof-of-concept involves a PEC bionanosystem comprising a NaYF4:Yb,Tm@NaYF4 upconversion nanoparticles (UCNPs) reporter, which is confined by DNA hybridization on a CdS quantum dots (QDs)/indium tin oxide (ITO) photoelectrode. The CdS QD-modified ITO electrode was powered by upconversion absorption together with energy transfer effect through UCNPs for a stable photocurrent generation. By measuring the photocurrent change, the target DNA could be detected in a specific and sensitive way with a wide linear range from 10 pM to 1 µM and a low detection limit of 0.1 pM. This work exploited the use of UCNPs as signal reporters and realized upconversion-powered PEC bioanalysis. Given the diversity of UCNPs, we believe it will offer a new perspective for the development of advanced upconversion-powered PEC bioanalysis.

Novel Nanocomposites for Luminescent Thermometry with Two Different Modalities.

In this work, we successfully integrated fluorescent nanodiamonds (FNDs) and lanthanide ion-doped upconversion nanoparticles (UCNPs) in a nanocomposite structure for simultaneous optical temperature sensing. The effective integration of FND and UCNP shells was confirmed by employing high-resolution TEM imaging, X-ray diffraction, and dual-excitation optical spectroscopy. Furthermore, the synthesized ND@UCNP nanocomposites were tested by making simultaneous optical temperature measurements, and the detected temperatures showed excellent agreement within their sensitivity limit. The simultaneous measurement of temperature using two different modalities having different sensing physics but with the same composite nanoparticles inside is expected to greatly improve the confidence of nanoscale temperature measurements. This should resolve some of the controversy surrounding nanoscale temperature measurements in biological applications.

Fabrication of Erbium-Doped Upconversion Nanoparticles and Carbon Quantum Dots for Efficient Perovskite Solar Cells.

Upconversion nanoparticles (UCNPs) and carbon quantum dots (CQDs) have emerged as promising candidates for enhancing both the stability and efficiency of perovskite solar cells (PSCs). Their rising prominence is attributed to their dual capabilities: they effectively passivate the surfaces of perovskite-sensitive materials while simultaneously serving as efficient spectrum converters for sunlight. In this work, we synthesized UCNPs doped with erbium ions as down/upconverting ions for ultraviolet (UV) and near-infrared (NIR) light harvesting. Various percentages of the synthesized UCNPs were integrated into the mesoporous layers of PSCs. The best photovoltaic performance was achieved by a PSC device with 30% UCNPs doped in the mesoporous layer, with PCE = 16.22% and a fill factor (FF) of 74%. In addition, the champion PSCs doped with 30% UCNPs were then passivated with carbon quantum dots at different spin coating speeds to improve their photovoltaic performance. When compared to the pristine PSCs, a fabricated PSC device with 30% UCNPs passivated with CQDs at a spin coating speed of 3000 rpm showed improved power conversion efficiency (PCE), from 16.65% to 18.15%; a higher photocurrent, from 20.44 mA/cm2 to 22.25 mA/cm2; and a superior fill factor (FF) of 76%. Furthermore, the PSCs integrated with UCNPs and CQDs showed better stability than the pristine devices. These findings clear the way for the development of effective PSCs for use in renewable energy applications.

Miniaturized Biosensors Based on Lanthanide-Doped Upconversion Polymeric Nanofibers.

Electrospun nanofibers possess a large surface area and a three-dimensional porous network that makes them a perfect material for embedding functional nanoparticles for diverse applications. Herein, we report the trends in embedding upconversion nanoparticles (UCNPs) in polymeric nanofibers for making an advanced miniaturized (bio)analytical device. UCNPs have the benefits of several optical properties, like near-infrared excitation, anti-Stokes emission over a wide range from UV to NIR, narrow emission bands, an extended lifespan, and photostability. The luminescence of UCNPs can be regulated using different lanthanide elements and can be used for sensing and tracking physical processes in biological systems. We foresee that a UCNP-based nanofiber sensing platform will open opportunities in developing cost-effective, miniaturized, portable and user-friendly point-of-care sensing device for monitoring (bio)analytical processes. Major challenges in developing microfluidic (bio)analytical systems based on UCNPs@nanofibers have been reviewed and presented.

Preparation and Characterization of Uniform and Controlled Silica Encapsulating on Lithium Yttrium Fluoride-Based Upconversion Nanoparticles.

In this work, we present an advancement in the encapsulation of lithium yttrium fluoride-based (YLiF4:Yb,Er) upconversion nanocrystals (UCNPs) with silica (SiO2) shells through a reverse microemulsion technique, achieving UCNPs@SiO2 core/shell structures. Key parameters of this approach were optimized to eliminate the occurrence of core-free silica particles and ensure a controlled silica shell thickness growth on the UCNPs. The optimal conditions for this method were using 6 mg of UCNPs, 1.5 mL of Igepal CO-520, 0.25 mL of ammonia, and 50 µL of tetraethyl orthosilicate (TEOS), resulting in a uniform silica shell around UCNPs with a thickness of 8 nm. The optical characteristics of the silica-encased UCNPs were examined, confirming the retention of their intrinsic upconversion luminescence (UC). Furthermore, we developed a reliable strategy to avoid the coencapsulation of multiple UCNPs within a single silica shell. This approach led to a tenfold increase in the UC luminescence of the annealed particles compared to their nonannealed counterparts, under identical silica shell thickness and excitation conditions. This significant improvement addresses a critical challenge and amplifies the applicability of the resulting UCNPs@SiO2 core/shell structures in various fields.

A "turn off-on" fluorescent sensor for detection of Cr(â ¥) based on upconversion nanoparticles and nanoporphyrin.

Hexavalent chromium (Cr(Ⅵ)) is a significant environmental pollutant because of its toxic and carcinogenic properties and wide use in various industries. Hence, there is an urgent need to develop accurate and selective approaches to detect the concentration of Cr(Ⅵ) in agricultural and aquaculture products to help humans avoid potential hazards of indirectly taking in Cr(Ⅵ). In this work, we report a "turn off-on" fluorescent sensor based on citric acid coated, 808 nm-excited core-shell upconversion nanoparticles (CA-UCNPs) and self-assembled copper porphyrin nanoparticles (nano CuTPyP) for sensitive and specific detection of Cr(Ⅵ). Nano copper 5, 10, 15, 20-tetra(4-pyridyl)-21H-23H- porphine obtained by acid-base neutralization micelle-confined self-assembly method function as an effective quencher due to its excellent optical property and water solubility. Through electrostatic interactions, positively charged nano CuTPyP are attracted to the surface of negatively charged CA-UCNPs, which can almost completely quench the fluorescence emission. In the presence of Cr(Ⅵ), nano CuTPyP can discriminatively interact with Cr(Ⅵ) and form nano CuTPyP/Cr(Ⅵ) complex, which separates nano CuTPyP from CA-UCNPs and restores the fluorescence. The sensing system exhibits a good linear response to Cr(Ⅵ) concentration in the range from 0.5 to 400 µM with a detection limit of 0.36 µM. The sensing method also displays high selectivity against other common ions including trivalent chromium and is applied to the analysis of Cr(Ⅵ) in actual rice and fish samples with satisfactory results.

NIR-promoted ferrous ion regeneration enhances ferroptosis for glioblastoma treatment.

Ferroptosis, a unique iron-dependent mode of cell death characterized by lipid peroxide accumulation, holds significant potential for the treatment of glioblastoma (GBM). However, the effectiveness of ferroptosis is hindered by the limited intracellular ferrous ions (Fe2+) and hydrogen peroxide (H2O2). In this study, a novel near-infrared (NIR)-light-responsive nanoplatform (ApoE-UMSNs-GOx/SRF) based on upconversion nanoparticles (UCNPs) was developed. A layer of mesoporous silica and a lipid bilayer were coated on UCNPs sequentially and loaded with glucose oxidase (GOx) and sorafenib, respectively. Further attachment of the ApoE peptide endowed the nanoplatform with BBB penetration and GBM targeting capabilities. Our results revealed that ApoE-UMSNs-GOx/SRF could efficiently accumulated in the orthotopic GBM and induce amplified ferroptosis when combining with NIR irradiation. The UCNPs mediated the photoreduction of Fe3+ to Fe2+ by converting NIR to UV light, and excess H2O2 was produced by the reaction of glucose with the loaded GOx. These processes greatly promoted the production of ROS, which together with inhibition of system Xc- by the loaded sorafenib, leading to enhanced accumulation of lipid peroxides and significantly improved the antiglioma effect both in vitro and in vivo. Our strategy has the potential to enhance the effectiveness of ferroptosis as a therapeutic approach for GBM.

Cold-Responsive Hyaluronated Upconversion Nanoplatform for Transdermal Cryo-Photodynamic Cancer Therapy.

Cryotherapy leverages controlled freezing temperature interventions to engender a cascade of tumor-suppressing effects. However, its bottleneck lies in the standalone ineffectiveness. A promising strategy is using nanoparticle therapeutics to augment the efficacy of cryotherapy. Here, a cold-responsive nanoplatform composed of upconversion nanoparticles coated with silica - chlorin e6 - hyaluronic acid (UCNPs@SiO2-Ce6-HA) is designed. This nanoplatform is employed to integrate cryotherapy with photodynamic therapy (PDT) in order to improve skin cancer treatment efficacy in a synergistic manner. The cryotherapy appeared to enhance the upconversion brightness by suppressing the thermal quenching. The low-temperature treatment afforded a 2.45-fold enhancement in the luminescence of UCNPs and a 3.15-fold increase in the photodynamic efficacy of UCNPs@SiO2-Ce6-HA nanoplatforms. Ex vivo tests with porcine skins and the subsequent validation in mouse tumor tissues revealed the effective HA-mediated transdermal delivery of designed nanoplatforms to deep tumor tissues. After transdermal delivery, in vivo photodynamic therapy using the UCNPs@SiO2-Ce6-HA nanoplatforms resulted in the optimized efficacy of 79% in combination with cryotherapy. These findings underscore the Cryo-PDT as a truly promising integrated treatment paradigm and warrant further exploring the synergistic interplay between cryotherapy and PDT with bright upconversion to unlock their full potential in cancer therapy.

Recent Advancement of Nanotheranostics in Cancer Applications.

The field of nanomedicine shows promising implications in the concurrent delivery of therapeutic and diagnostic (theranostics) compounds in a single platform. Nanotheranostics is incredibly promising since it offers simultaneous non-invasive disease detection and treatment together with the exciting ability to track drug release and distribution in real-time, thereby forecasting and evaluating the efficacy of the therapy. The cancer theranostic approach improves the cancer prognosis safely and effectively. Common classes of nanoscale biomaterials, including magnetic nanoparticles, quantum dots, upconversion nanoparticles, mesoporous silica nanoparticles, carbon- based nanoparticles, and organic dye-based nanoparticles, have demonstrated enormous potential for theranostic activity. The need for improved disease detection and enhanced chemotherapeutic treatments, together with realistic considerations for clinically translatable nanomaterials will be key driving factors for theranostic agent research shortly. The developments of precision theranostic nanomaterials are employed in imaging systems like, MRI, PET, and SPECT with multifunctional ability. In this review, different nanoparticles/nanomaterials that are used/developed for theranostic activity are discussed.

Dual-mode upconversion sensors for detecting differently charged biotargets based on the oxidase-mimicking activity of Ce4+ and electrostatic control.

Heparin is a highly negatively charged sulfated linear polymer glycosaminoglycan that has been widely used as an anticoagulant in medicine. Protamine is a cationic protein rich in arginine that is used to treat the blood-brain barrier during excess heparin surgery. Trypsin is the most important digestive enzyme-encoding generated by the pancreas and can specifically cleave the carboxyl ends of arginine and lysine residues. Heparin, protamine, and trypsin interact and constrain each other, and their fluctuations reflect the body's dysfunction. Therefore, it is necessary to develop a fast, sensitive, and highly selective assay for regularly monitoring the levels of heparin, protamine, and trypsin in serum. Herein, a fluorescent and colorimetric dual-mode upconversion nanoparticle (UCNP) biosensor was used for the determination of heparin, protamine, and trypsin based on the oxidase-mimicking activity of Ce4+ and electrostatic control. The biosensor exhibited sensitive detection of heparin, protamine, and trypsin with low limits of detection (LODs) of 16 ng/mL, 87 ng/mL and 31 ng/mL, respectively. Furthermore, the designed biosensor could eliminate autofluorescence, which not only effectively increased the accuracy of the sensor but also provided a new sensing pathway for the detection of differently charged biotargets.

Natural and polyanionic heparin polysaccharide functionalized upconversion nanoparticles for highly sensitive and selective ratiometric detection of pesticide.

Pesticide contamination is a global concern, threatening human health and food safety. Herein, we developed heparin (HEP) functionalized upconversion nanoparticles (UCNPs)-based ratiometric nanosensor for the sensitive detection of 2,6-dichloro-4-nitroaniline (DCN) pesticide via inner filter effect. The strategy for HEP functionalization of UCNPs is based on adjusting the surface potentials of UCNPs with polyanionic HEP through the electrostatic interaction. UCNPs (NaYbF4:Gd/Y/Tm@NaYbF4@NaYF4) was designed with core-shell-shell structure and extra sensitizer layer for efficient and strong upconversion luminescence (UCL) in the range of UV to NIR. After incorporation of DCN, the upconverted UV emission of UCNPs-HEP ratiometric nanosensor was considerably quenched with the NIR UCL at 800 nm remaining unchanged as internal standard. The UCNPs-HEP ratiometric nanosensor can achieve outstandingly selective and sensitive detection of DCN at the wide linear range of 5-300 µM with a detection limit of 0.41 µM. The remarkable applicability of the UCNPs-HEP ratiometric nanosensor was verified in apple, cucumber and grapes samples. The developed UCNPs-HEP ratiometric nanosensor with excellent biocompatibility and water dispersion capability, is promising for convenient, selective and sensitive sensing of DCN towards food and aqueous samples.

Three-dimensional, dual-color nanoscopy enabled by migrating photon avalanches with one single low-power CW beam.

The development of super-resolution fluorescence microscopy is very essential for understanding the physical and biological fundamentals at nanometer scale. However, to date most super-resolution modalities require either complicated/costly purpose-built systems such as multiple-beam architectures or complex post-processing procedures with intrinsic artifacts. Achieving three-dimensional (3D) or multi-channel sub-diffraction microscopic imaging using a simple method remains a challenging and struggling task. Herein, we proposed 3D highly-nonlinear super-resolution microscopy using a single-beam excitation strategy, and the microscopy principle was modelled and studied based on the ultrahigh nonlinearity enabled by photon avalanches. According to the simulation, the point spread function of highly nonlinear microscopy is switchable among different modes and can shrink three-dimensionally to sub-diffraction scale at the photon avalanche mode. Experimentally, we demonstrated 3D optical nanoscopy assisted with huge optical nonlinearities in a simple laser scanning configuration, achieving a lateral resolution down to 58 nm (λ/14) and an axial resolution down to 185 nm (λ/5) with one single beam of low-power, continuous-wave, near-infrared laser. We further extended the photon avalanche effect to many other emitters to develop multi-color photon avalanching nanoprobes based on migrating photon avalanche mechanism, which enables us to implement single-beam dual-color sub-diffraction super-resolution microscopic imaging.

A fluorescent sensor based on single band bright red luminescent core-shell UCNPs for the high-sensitivity detection of glucose and glutathione.

As the reliable biomarkers to evaluate the diabetes and neurological disease, sensitive and accurate detection of glucose and glutathione (GSH) in biological samples is necessary for early precaution and diagnosis of related-diseases. The single red upconversion nanoparticles (UCNPs) especially with core-shell structure can penetrate deeper biological tissues and cause less energy loss and thus have higher sensitivity and accuracy. Additionally, an enzyme-controlled cascade signal amplification (ECSAm) strategy will further enhance sensitivity. Herein, using single red UCNPs with core-shell structure as the luminescent material, a fluorescent sensor based on ECSAm was developed for the highly sensitive and accurate detection of glucose and GSH. Under the optimal conditions, the limits of detection for glucose and GSH by fluorescent method were 0.03 µM and 0.075 µM, separately. This assay was used to analyze the content of glucose and GSH in serum samples, and the obtained data was close to that of commercial blood glucose and GSH detection kit. The developed sensor platform based on single red UCNPs with core-shell structure and ECSAm can be a promising method for the accurate and sensitive detection of glucose and GSH in biological samples.