Customized Enhancement of Thermal Sensitivity of Tumors at Different Subcutaneous Depths by Multichannel Lanthanide Nanocomposites.

The photothermal therapeutic effect on tumors located at different subcutaneous depths varies due to the attenuation of light by tissue. Here, based on the wavelength-dependent optical attenuation properties of tissues, the tumor depth is assessed using a multichannel lanthanide nanocomposite. A zeolitic imidazolate framework (ZIF-8)-coated nanocomposite is able to deliver high amounts of the hydrophilic heat shock protein 90 inhibitor epigallocatechin gallate through a hydrogen-bonding network formed by the encapsulated highly polarized polyoxometalate guest. It is superior to both bare and PEGylated ZIF-8 for drug delivery. With the assessment of tumor depth and accumulated amount of nanocomposite by fluorescence, an irradiation prescription can be customized to release sufficient HSP90 inhibitor and generate heat for sensitized photothermal treatment of tumors, which not only ensured therapeutic efficacy but also minimized damage to the surrounding tissues.

Lanthanide luminescence nanothermometer with working wavelength beyond 1500 nm for cerebrovascular temperature imaging in vivo.

Nanothermometers enable the detection of temperature changes at the microscopic scale, which is crucial for elucidating biological mechanisms and guiding treatment strategies. However, temperature monitoring of micron-scale structures in vivo using luminescent nanothermometers remains challenging, primarily due to the severe scattering effect of biological tissue that compromises the imaging resolution. Herein, a lanthanide luminescence nanothermometer with a working wavelength beyond 1500 nm is developed to achieve high-resolution temperature imaging in vivo. The energy transfer between lanthanide ions (Er3+ and Yb3+) and H2O molecules, called the environment quenching assisted downshifting process, is utilized to establish temperature-sensitive emissions at 1550 and 980 nm. Using an optimized thin active shell doped with Yb3+ ions, the nanothermometer's thermal sensitivity and the 1550 nm emission intensity are enhanced by modulating the environment quenching assisted downshifting process. Consequently, minimally invasive temperature imaging of the cerebrovascular system in mice with an imaging resolution of nearly 200 µm is achieved using the nanothermometer. This work points to a method for high-resolution temperature imaging of micron-level structures in vivo, potentially giving insights into research in temperature sensing, disease diagnosis, and treatment development.

An NIR-IIb emissive transmembrane voltage nano-indicator for the optical monitoring of electrophysiological activities in vivo.

In vivo transmembrane-voltage detection reflected the electrophysiological activities of the biological system, which is crucial for the diagnosis of neuronal disease. Traditional implanted electrodes can only monitor limited regions and induce relatively large tissue damage. Despite emerging monitoring methods based on optical imaging have access to signal recording in a larger area, the recording wavelength of less than 1000 nm seriously weakens the detection depth and resolution in vivo. Herein, a Förster resonance energy transfer (FRET)-based nano-indicator, NaYbF4:Er@NaYF4@Cy7.5@DPPC (Cy7.5-ErNP) with emission in the near-infrared IIb biological window (NIR-IIb, 1500-1700 nm) is developed for transmembrane-voltage detection. Cy7.5 dye is found to be voltage-sensitive and is employed as the energy donor for the energy transfer to the lanthanide nanoparticle, NaYbF4:Er@NaYF4 (ErNP), which works as the acceptor to achieve electrophysiological signal responsive NIR-IIb luminescence. Benefiting from the high penetration and low scattering of NIR-IIb luminescence, the Cy7.5-ErNP enables both the visualization of action potential in vitro and monitoring of Mesial Temporal lobe epilepsy (mTLE) disease in vivo. This work presents a concept for leveraging the lanthanide luminescent nanoprobes to visualize electrophysiological activity in vivo, which facilitates the development of an optical nano-indicator for the diagnosis of neurological disorders.

Focused Ultrasound-Responsive Nanocomposite with Near-Infrared II Mechanoluminescence for Spatiotemporally Selective Immune Activation in Lymph Nodes.

The immune regulation of the lymphatic system, especially the lymph node (LN), is of great significance for the treatment of diseases and the inhibition of pathogenic organisms spreading in the body. However, achieving precise spatiotemporal control of immune cell activation in LN in vivo remains a challenge due to tissue depth and off-target effects. Furthermore, minimally invasive and real-time feedback methods to monitor the regulation of the immune system in LN are lacking. Here, focused ultrasound responsive immunomodulator loaded nanoplatform (FURIN) with near-infrared II (NIR-II) luminescence is designed to achieve spatiotemporally controllable immune activation in LN in vivo. The NIR-II persistent luminescence of FURIN can track its delivery in LN through bioimaging. Under focused ultrasound (FUS) stimulation, the immunomodulator encapsulated in FURIN can be released locally in the LN to activate immune cells such as dendritic cells and the NIR-II mechanoluminescence of FURIN provides real-time optical feedback signals for immune activation. This work points to a FUS mediated, spatiotemporal selective immune activation strategy in vivo with the feedback control of luminescence signals via ultrasound responsive nanocomposite, which is of great significance in improving the efficacy and reducing the side effect of immune regulation for the development of potential immunotherapeutic methods in the future.

A bone-targeting near-infrared luminescence nanocarrier facilitates alpha-ketoglutarate efficacy enhancement for osteoporosis therapy.

Osteoporosis (OP), which largely increases the risk of fractures, is the most common chronic degenerative orthopedic disease in the elderly due to the imbalance of bone homeostasis. Alpha-ketoglutaric acid (AKG), an endogenous metabolic intermediate involved in osteogenesis, plays critical roles in osteogenic differentiation and mineralization and the inhibition of osteoclastogenic differentiation. However, the low bioavailability and poor bone-targeting efficiency of AKG seriously limit its efficacy in OP treatment. In this work, a bone-targeting, near-infrared emissive lanthanide luminescence nanocarrier loaded with AKG (ß-NaYF4:7%Yb, 60%Nd@NaLuF4@mSiO2-EDTA-AKG, abbreviated as LMEK) is developed for the enhancement of AKG efficacy in OP therapy. By utilizing the NIR-II luminescence (>1000 nm) of LMEK, whole-body bone imaging with high spatial resolution is achieved to confirm the bone enrichment of AKG noninvasively in vivo. The results reveal that LMEK exhibits a remarkable OP therapeutic effect in improving the osseointegration of the surrounding bone in the ovariectomized OP mice models, which is validated by the enhanced inhibition of osteoclast through hypoxia-inducible factor-1α suppression and promotion of osteogenic differentiation in osteoblast. Notably, the dose of AKG in LMEK can be reduced to only 0.2 % of the dose when pure AKG is used in therapy, which dramatically improves the bioavailability of AKG and mitigates the metabolism burden. This work provides a strategy to conquer the low utilization of AKG in OP therapy, which not only overcomes the challenges in AKG efficacy for OP treatment but also offers insights into the development and application of other potential drugs for skeletal diseases. STATEMENT OF SIGNIFICANCE: Alpha-ketoglutarate (AKG) is an intermediate within the Krebs cycle, participating in diverse metabolic and cellular processes, showing potential for osteoporosis (OP) therapy. However, AKG's limited bioavailability and inefficient bone-targeting hinder its effectiveness in treating OP. Herein, a near-infrared emissive nanocarrier is developed that precisely targets bones and delivers AKG, bolstering its effectiveness in OP therapy. Thanks to this efficient bone-targeting delivery, the AKG dosage is reduced to 0.2 % of the conventional treatment level. This marks the first utilization of a bone-targeting nanocarrier to amplify AKG's bioavailability and OP therapy efficacy. Furthermore, the mechanism of AKG-loaded nanocarrier regulating the biological behavior of osteoclasts and osteoblasts mediated is tentatively explored.

Multifunctional Optical Tomography System With High-Fidelity Surface Extraction Based on a Single Programmable Scanner and Unified Pinhole Modeling.

OBJECTIVE: Macroscopic optical tomography is a non-invasive method that can visualize the 3D distribution of intrinsic optical properties or exogenous fluorophores, making it highly attractive for small animal imaging. However, reconstructing the images requires prior knowledge of surface information. To address this, existing systems often use additional hardware components or integrate multimodal information, which is expensive and introduces new issues such as image registration. Our goal is to develop a multifunctional optical tomography system that can extract surface information using a concise hardware design. METHODS: Our proposed system uses a single programmable scanner to implement both surface extraction and optical tomography functions. A unified pinhole model is used to describe both the illumination and detection procedures for capturing 3D point cloud. Line-shaped scanning is adopted to improve both spatial resolution and speed of surface extraction. Finally, we integrate the extracted surface information into the optical tomographic reconstruction to more accurately map the fluorescence distribution. RESULT: Comprehensive phantom experiments with different levels of complexity were designed to evaluate the performance of surface extraction and fluorescence tomography. We also imaged the axillary lymph nodes in living mice after injection of fluorophore, demonstrating the proposed system facilitates more reliable fluorescence tomography. CONCLUSION: We have successfully developed a versatile optical tomography system by leveraging concise hardware design and unified pinhole modeling. Phantom validation demonstrates that our system provides high-precision surface information with a maximum error of 0.1 mm, while the surface-guided FMT reconstruction is more reliable than the blind reconstruction using simplified surface geometry, elevating several quantitative metrics including RMSE, CNR, and Dice. SIGNIFICANCE: Our work explores the feasibility of obtaining additional surface information using existing components of standalone optical tomography. This makes the optical tomographic technique more accurate and more accessible to biomedical researchers.

Near Infrared Emissive Lanthanide Luminescence Nanoparticle Used in Early Diagnosis and Brain Temperature Detection for Ischemic Stroke.

Ischemic stroke (IS) is one of the most dangerous medical conditions resulting in high mortality and morbidity. The increased brain temperature after IS is closely related to prognosis, making it highly significant for the early diagnosis and the progression evaluation of IS. Herein, a temperature-responsive near infrared (NIR) emissive lanthanide luminescence nanoparticle is developed for the early diagnosis and brain temperature detection of IS. After intravenous injection, the nanoparticles can pass through the damaged blood-brain barrier of the ischemic region, allowing the extravasation and enrichment of nanoparticles into the ischemic brain tissue. The NIR luminescence signals of the nanoparticles are used not only to judge the location and severity of the cerebral ischemic injury but also to report the brain temperature variation in the ischemic area through a visualized way. The results show that the designed nanoparticles can be used for the early diagnosis of ischemic stroke and minimally invasive temperature detection of cerebral ischemic tissues in transient middle cerebral artery occlusion mice model, which is expected to make the clinical diagnosis of ischemic stroke more rapid and convenient, more accurately evaluate the state of brain injury in stroke patients and also guide stroke hypothermia treatment.

Recyclable and Robust Optical Nanoprobes with Engineered Enzymes for Sustainable Serodiagnostics.

Recyclable fluorescence assays that can be stored at room temperature would greatly benefit biomedical diagnostics by bringing sustainability and cost-efficiency, especially for point-of-care serodiagnostics in developing regions. Here, a general strategy is proposed to generate recyclable fluorescent probes by using engineered enzymes with enhanced thermo-/chemo-stability, which maintains an outstanding serodiagnostic performance (accuracy >95%) after 10 times of recycling as well as after storage at elevated temperatures (37 °C for 10 days). With these three outstanding properties, recyclable fluorescent probes can be designed to detect various biomarkers of clinical importance by using different enzymes.

An erythrocyte membrane-modified biomimetic synergistic nanosystem for cancer anti-vascular therapy and initial efficacy monitoring.

Tumor vascular disruption has become a promising strategy for cancer therapy in recent decades. Nanocomposites loaded with therapeutic materials and drugs are expected to improve the accuracy of anti-vascular therapy and minimize side effects. However, how to prolong blood circulation of therapeutic nanocomposites for enhanced accumulation in tumor vasculature and how to monitor the initial efficacy of anti-vascular therapy for early evaluation of prognosis remain unsolved. Herein, a biomimetic nanosystem consisting of erythrocyte membrane modified nanocomposites (CMNCs) is developed for cooperation to achieve anti-vascular cancer therapy and initial efficacy monitoring. By utilizing poly(lactic-co-glycolic acid) (PLGA) as the interface material, functional nanomaterials and drug molecules are successfully integrated into CMNCs. The long circulation and immune escape features of the erythrocyte membrane facilitate CMNCs loaded with photothermal agents and chemodrugs to be delivered to the tumor region for anti-vascular treatment. Furthermore, the vascular damage-induced haemorrhage and the following coagulation process is labelled by near infrared emissive CMNCs to indicate the initial therapeutic efficacy of the treatment. This work not only points to a biomimetic strategy for conquering the challenges in anti-vascular cancer therapy, but also provides insights into the biological responses of erythrocyte membrane modified nanocomposites to exploit their biomedical applications.

Intelligent Health Assessment of Aviation Bearing Based on Deep Transfer Graph Convolutional Networks under Large Speed Fluctuations.

As a critical support and fixed component of aero engines, electro-hydrostatic actuators, and other equipment, the operation of aviation bearings is often subject to high speed, high-temperature rise, large load, and other continuous complex fluctuation conditions, which makes their health assessment tasks more difficult. To solve this problem, an intelligent health assessment method based on a new Deep Transfer Graph Convolutional Network (DTGCN) is proposed for aviation bearings under large speed fluctuation conditions. First, a new DTGCN algorithm is designed, which mainly uses the domain adaptation mechanism to enhance the performance of Graph Convolutional Network (GCN) and the generalization performance of transfer properties. Specifically, order spectrum analysis is employed to resample the vibration signals of aviation bearings and transform them into order spectral signals. Then, the trained 1dGCN is used as the feature extractor, and the designed Dynamic Multiple Kernel Maximum Mean Discrepancy (DMKMMD) is calculated to match the difference in edge distribution. Finally, the aligned features are fed into the softmax classifier for intelligent health assessment. The effectiveness of the proposed diagnostic algorithm and method are validated by using aviation bearing fault data set under large speed fluctuation conditions.

Multi-Channel Lanthanide Nanocomposites for Customized Synergistic Treatment of Orthotopic Multi-Tumor Cases.

Simultaneous photothermal ablation of multiple tumors is limited by unpredictable photo-induced apoptosis, caused by individual intratumoral differences. Here, a multi-channel lanthanide nanocomposite was used to achieve tailored synergistic treatment of multiple subcutaneous orthotopic tumors under non-uniform whole-body infrared irradiation prescription. The nanocomposite reduces intratumoral glutathione by simultaneously activating the fluorescence and photothermal channels. The fluorescence provides individual information on different tumors, allowing customized prescriptions to be made. This enables optimal induction of hyperthermia and dosage of chemo drugs, to ensure treatment efficacy, while avoiding overtherapy. With an accessional therapeutic laser system, customized synergistic treatment of subcutaneous orthotopic cancer cases with multiple tumors is possible with both high efficacy and minimized side effects.

Hydrogel platform capable of molecularly resolved pulling on cells for mechanotransduction.

The active forces exerted from the extracellular matrix (ECM) to mechanoreceptors have crucial impact on many cell functions and disease development. However, our understanding of the underlying mechanisms is held back due to the lack of ECM mimicking platform able to apply molecularly resolved forces to cells. Herein, we present novel hydrogel platform capable of generate pN range forces to specific cellular receptors, at molecular scale. This capability was achieved through near-infrared (NIR) light regulated macromolecular actuators functionalized within the platform. This platform enables us to reveal cell responses to molecularly resolved forces under controlled magnitude (150-400 â€‹pN) and frequency (up to 100 â€‹Hz) on matrix with varied stiffness. We find the stiffness of the matrix has a large influence on the applied force transduction to cells. This versatile platform holds the potential for establishing correlation between receptor signaling pathways and cellular responses closer to physiological conditions.

Dual-channel lanthanide-doped nanoprobe for reliable multi-signal ratiometric detection of H2S in whole blood.

Wavelength-dependent absorbance of blood has impeded the development of fluorescence biodetection in whole blood. Here, by replacing the fluorescence working signal with a temperature signal, reliable H2S detection was performed in samples of whole blood. The developed system was based on a dual-channel lanthanide-doped nanoprobe, which further allowed precise serodiagnosis of acute pancreatitis.

A lanthanide nanocomposite with cross-relaxation enhanced near-infrared emissions as a ratiometric nanothermometer.

Lanthanide luminescence nanothermometers (LNTs) provide microscopic, highly sensitive, and visualizable optical signals for reporting temperature information, which is particularly useful in biomedicine to achieve precise diagnosis and therapy. However, LNTs with efficient emissions at the long-wavelength region of the second and the third near-infrared (NIR-II/III) biological window, which is more favourable for in vivo thermometry, are still limited. Herein, we present a lanthanide-doped nanocomposite with Tm3+ and Nd3+ ions as emitters working beyond 1200 nm to construct a dual ratiometric LNT. The cross-relaxation processes among lanthanide ions are employed to establish a strategy to enhance the NIR emissions of Tm3+ for bioimaging-based temperature detection in vivo. The dual ratiometric probes included in the nanocomposite have potential in monitoring the temperature difference and heat transfer at the nanoscale, which would be useful in modulating the heating operation more precisely during thermal therapy and other biomedical applications. This work not only provides a powerful tool for temperature sensing in vivo but also proposes a method to build high-efficiency NIR-II/III lanthanide luminescent nanomaterials for broader bio-applications.

Lanthanide Luminescent Nanocomposite for Non-Invasive Temperature Monitoring in Vivo.

Temperature monitoring in vivo plays a vital role in the investigation of biological processes of organisms and the improvement of disease theranostic methods. The development of lanthanide luminescent nanocomposite-derived temperature probes in vivo allows accurate and reliable interrogation of biological thermodynamic processes due to their superior photostability, high sensitivity, and non-invasive sensing fashion. This concept presented an overview of the recent development of lanthanide luminescent nanocomposite which are suitable for in vivo temperature monitoring, including the thermometric principles, key features, materials designs as well as their potential biomedical applications for non-invasive temperature detection in the living body. The perspectives of these lanthanide luminescent nanocomposite thermometers for the optimization of temperature monitoring performance and potential future development are also discussed.

Customized Photothermal Therapy of Subcutaneous Orthotopic Cancer by Multichannel Luminescent Nanocomposites.

Photothermal therapy (PTT) is a potentially advanced strategy for highly precise cancer treatment. Tumor-microenvironment-activatable agents provide useful tools for PTT, but their photothermal conversion capacities vary and cannot be evaluated in vivo; thus, a general PTT prescription does not work with individual activatable agents. Here, glutathione (GSH)-activatable nanocomposites, silicomolybdate-functionalized NaLuF4 :Yb,Er@NaLuF4 @NaLuF4 :Nd are prepared, for customized PTT of subcutaneous orthotopic cancer. By simultaneously determining intratumoral GSH concentration and the amount of accumulated agent using multiple orthogonal luminescent emissions of nanocomposites, near-infrared absorbance of photothermal conversion agents is evaluated in vivo, based on the optimized irradiating prescriptions (irradiating power density and time) established. This allows customized PTT of each individual case with high efficacy and viability. This work also includes a method for investigating individual intratumoral variation, and the development of the next generation of customized nanomedicine for efficacious PTT of subcutaneous orthotopic cancer.

EDTA-Modified 17ß-Estradiol-Laden Upconversion Nanocomposite for Bone-Targeted Hormone Replacement Therapy for Osteoporosis.

Hormone therapy (HT) is one of the most effective treatments for osteoporosis. However, the nonselective accumulation of hormone in organs such as breast, heart and uterus other than bones causes serious side effects, which impedes the application of HT. Hence, it is critically important to develop a HT strategy with reduced non-specific enrichment of hormone drugs in non-target tissues and enhanced bone-targeting ability. Methods: Herein, a 17ß-estradiol (E2)-laden mesoporous silica-coated upconversion nanoparticle with a surface modification of ethylenediaminetetraacetic acid (EDTA) (NaLuF4:Yb,Tm@NaLuF4@mSiO2-EDTA-E2, E2-csUCNP@MSN-EDTA) is developed for bone-targeted osteoporosis hormone therapy. EDTA was attached onto the surface of E2 upconversion nanocomposite to enhance its affinity and efficiency targeting bone tissue and cells to optimize hormone replacement therapy for osteoporosis. We characterized the size, cytotoxicity, loading and release efficiency, in situ and ex vivo imaging. Further, in vitro and in vivo osteogenic ability was tested using preosteoblast and ovariectomy mouse model of osteoporosis. Results: The upconversion core of E2-csUCNP@MSN-EDTA nanoparticle serves as an excellent imaging agent for tracking the loaded hormone drug in vivo. The mesoporous silica layer has a high loading efficiency for E2 and provides a relatively long-lasting drug release within 50 h. EDTA anchored on the silica layer endows the nanocomposite with a bone targeting property. The nanocomposite effectively reverses estrogen deficiency-induced osteoporosis and reduces the damage of hormone to the uterus. The bone mineral density in the nanocomposite treatment group is nearly twice that of the ovariectomized (OVX) group. Compared with the E2 group, the uterine weight and luminal epithelial height were significantly lower in the nanocomposite treatment group. Conclusion: This work demonstrated that E2-csUCNP@MSN-EDTA alleviates the side effect of hormone therapy while maintaining its therapeutic efficacy, which has great potential for developing the next generation of methods for osteoporosis treatment.

Theranostic nanoparticles enabling the release of phosphorylated gemcitabine for advanced pancreatic cancer therapy.

Gemcitabine (GEM) has been the recommended first-line drug for patients with pancreatic ductal adenocarcinoma cancer (PDAC) for the last twenty years. However, GEM-based treatment has failed in many patients because of the drug resistance acquired during tumorigenesis and development. To override resistance to GEM in pancreatic cancer, we developed a visualisable, photothermally controlled, drug release nanosystem (VPNS). This nanosystem has NaLuF4:Nd@NaLuF4 nanoparticles as the luminescent core, octabutoxyphthalocyanine palladium(ii) (PdPc) as the photothermal agent, and phosphorylated gemcitabine (pGEM) as the chemodrug. pGEM, one of the active forms of GEM, can circumvent the insufficient activation of GEM in cancer cell metabolism. The NaLuF4:Nd@NaLuF4 nanoparticles were employed to visualise the tumor lesion in vivo by their near-infrared luminescence. The near-infrared light-triggered photothermal effect from PdPc could trigger the release of pGEM loaded in a thermally responsive ligand and simultaneously enable photothermal cancer treatment. This work presents an effective method that suppresses the growth of tumour cells with dual-mode treatment and enables the improved treatment of orthotopic nude mice afflicted with pancreatic cancer.

Pro-efferocytic nanoparticles are specifically taken up by lesional macrophages and prevent atherosclerosis.

Atherosclerosis is the process that underlies heart attack and stroke. A characteristic feature of the atherosclerotic plaque is the accumulation of apoptotic cells in the necrotic core. Prophagocytic antibody-based therapies are currently being explored to stimulate the phagocytic clearance of apoptotic cells; however, these therapies can cause off-target clearance of healthy tissues, which leads to toxicities such as anaemia. Here we developed a macrophage-specific nanotherapy based on single-walled carbon nanotubes loaded with a chemical inhibitor of the antiphagocytic CD47-SIRPα signalling axis. We demonstrate that these single-walled carbon nanotubes accumulate within the atherosclerotic plaque, reactivate lesional phagocytosis and reduce the plaque burden in atheroprone apolipoprotein-E-deficient mice without compromising safety, and thereby overcome a key translational barrier for this class of drugs. Single-cell RNA sequencing analysis reveals that prophagocytic single-walled carbon nanotubes decrease the expression of inflammatory genes linked to cytokine and chemokine pathways in lesional macrophages, which demonstrates the potential of 'Trojan horse' nanoparticles to prevent atherosclerotic cardiovascular disease.

Ratiometric upconversion nanothermometry with dual emission at the same wavelength decoded via a time-resolved technique.

The in vivo temperature monitoring of a microenvironment is significant in biology and nanomedicine research. Luminescent nanothermometry provides a noninvasive method of detecting the temperature in vivo with high sensitivity and high response speed. However, absorption and scattering in complex tissues limit the signal penetration depth and cause errors due to variation at different locations in vivo. In order to minimize these errors and monitor temperature in vivo, in the present work, we provided a strategy to fabricate a same-wavelength dual emission ratiometric upconversion luminescence nanothermometer based on a hybrid structure composed of upconversion emissive PbS quantum dots and Tm-doped upconversion nanoparticles. The ratiometric signal composed of two upconversion emissions working at the same wavelength, but different luminescent lifetimes, were decoded via a time-resolved technique. This nanothermometer improved the temperature monitoring ability and a thermal resolution and sensitivity of ~0.5 K and ~5.6% K-1 were obtained in vivo, respectively.