X-ray Activated Nanoprodrug for Visualization of Cortical Microvascular Alterations and NIR-II Image-Guided Chemo-Radiotherapy of Glioblastoma.

The permeability of the highly selective blood-brain barrier (BBB) to anticancer drugs and the difficulties in defining deep tumor boundaries often reduce the effectiveness of glioma treatment. Thus, exploring the combination of multiple treatment modalities under the guidance of second-generation near-infrared (NIR-II) window fluorescence (FL) imaging is considered a strategic approach in glioma theranostics. Herein, a hybrid X-ray-activated nanoprodrug was developed to precisely visualize the structural features of glioma microvasculature and delineate the boundary of glioma for synergistic chemo-radiotherapy. The nanoprodrug comprised down-converted nanoparticle (DCNP) coated with X-ray sensitive poly(Se-Se/DOX-co-acrylic acid) and targeted Angiopep-2 peptide (DCNP@P(Se-DOX)@ANG). Because of its ultrasmall size and the presence of DOX, the nanoprodrug could easily cross BBB to precisely monitor and localize glioblastoma via intracranial NIR-II FL imaging and synergistically administer antiglioblastoma chemo-radiotherapy through specific X-ray-induced DOX release and radiosensitization. This study provides a novel and effective strategy for glioblastoma imaging and chemo-radiotherapy.

Combination of Molecule-Targeted Therapy and Photodynamic Therapy Using Nanoformulated Verteporfin for Effective Uveal Melanoma Treatment.

Uveal melanoma (UM) is the most common primary ocular malignancy in adults and has high mortality. Recurrence, metastasis, and therapeutic resistance are frequently observed in UM, but no beneficial systemic therapy is available, presenting an urgent need for developing effective therapeutic drugs. Verteporfin (VP) is a photosensitizer and a Yes-Associated Protein (YAP) inhibitor that has been used in clinical practice. However, VP's lack of tumor targetability, poor biocompatibility, and relatively low treatment efficacy hamper its application in UM management. Herein, we developed a biocompatible CD44-targeting hyaluronic acid nanoparticle (HANP) carrying VP (HANP/VP) to improve UM treatment efficacy. We found that HANP/VP showed a stronger inhibitory effect on cell proliferation than that of free VP in UM cells. Systemic delivery of HANP/VP led to targeted accumulation in the UM-tumor-bearing mouse model. Notably, HANP/VP mediated photodynamic therapy (PDT) significantly inhibited UM tumor growth after laser irradiation compared with no treatment or free VP treatment. Consistently, in HANP/VP treated tumors after laser irradiation, the tumor proliferation and YAP expression level were decreased, while the apoptotic tumor cell and CD8+ immune cell levels were elevated, contributing to effective tumor growth inhibition. Overall, the results of this preclinical study showed that HANP/VP is an effective nanomedicine for tumor treatment through PDT and inhibition of YAP in the UM tumor mouse model. Combining phototherapy and molecular-targeted therapy offers a promising approach for aggressive UM management.

Synthesis and Preliminary Study of 99mTc-Labeled HYNIC-FAPi for Imaging of Fibroblast Activation Proteins in Tumors.

Fibroblast activation protein (FAP) is an emerging target for cancer diagnosis. Different types of FAP inhibitor (FAPI)-based radiotracers have been developed and applied for tumor imaging. However, few FAPI tracers for single photon emission computed tomography (SPECT) imaging have been reported. SPECT imaging is less expensive and more widely distributed than positron emission tomography (PET), and thus, 99mTc-labeled FAPIs would be more available to patients in developing regions. Herein, we developed a FAPI-04-derived radiotracer, HYNIC-FAPi-04 (HFAPi), for SPECT imaging. 99mTc-HFAPi, with a radiochemical purity of >98%, was prepared using a kit formula within 30 min. The specificity of 99mTc-HFAPi for FAP was validated by a cell binding assay in vitro and SPECT/CT imaging in vivo. The binding affinity (Kd value) of 99mTc-HFAPi for human FAP and murine FAP was 4.49 and 2.07 nmol/L, respectively. SPECT/CT imaging in HT1080-hFAP tumor-bearing mice showed the specific FAP targeting ability of 99mTc-HFAPi in vivo. In U87MG tumor-bearing mice, 99mTc-HFAPi had a higher tumor uptake compared with that of HT1080-hFAP and 4T1-mFAP tumor models. Interestingly, 99mTc-HFAPi showed a relatively high uptake in some murine joints. 99mTc-HFAPi accumulated in tumor lesions with a high tumor-to-background ratio. A preliminary clinical study was also performed in breast cancer patients. Additionally, 99mTc-HFAPi exhibited an advantage over 18F-FDG in the detection of lymph node metastatic lesions in breast cancer patients, which is helpful in improving treatment strategies. In short, 99mTc-HFAPi showed excellent affinity and specificity for FAP and is a promising SPECT radiotracer for (re)staging and treatment planning of breast cancers.

Molecular radio afterglow probes for cancer radiodynamic theranostics.

X-ray-induced afterglow and radiodynamic therapy tackle the tissue penetration issue of optical imaging and phototherapy. However, inorganic nanophosphors used in this therapy have their radio afterglow dynamic function as always on, limiting the detection specificity and treatment efficacy. Here we report organic luminophores (IDPAs) with near-infrared afterglow and 1O2 production after X-ray irradiation for cancer theranostics. The in vivo radio afterglow of IDPAs is >25.0 times brighter than reported inorganic nanophosphors, whereas the radiodynamic production of 1O2 is >5.7 times higher than commercially available radio sensitizers. The modular structure of IDPAs permits the development of a smart molecular probe that only triggers its radio afterglow dynamic function in the presence of a cancer biomarker. Thus, the probe enables the ultrasensitive detection of a diminutive tumour (0.64 mm) with superb contrast (tumour-to-background ratio of 234) and tumour-specific radiotherapy for brain tumour with molecular precision at low dosage. Our work reveals the molecular guidelines towards organic radio afterglow agents and highlights new opportunities for cancer radio theranostics.

Ultrasound-Activated NIR Chemiluminescence for Deep Tissue and Tumor Foci Imaging.

Fluorescence imaging requires real-time external light excitation; however, it has the drawbacks of autofluorescence and shallower penetration depth, limiting its application in deep tissue imaging. At the same time, ultrasound (US) has high spatiotemporal resolution, deep penetrability, noninvasiveness, and precise localization of lesions; thus, it can be a promising alternative to light. However, US-activated luminescence has been rarely reported. Herein, an US-activated near-infrared (NIR) chemiluminescence (CL) molecule, namely, PNCL, is designed by protoporphyrin IX as a sonosensitizer moiety and a phenoxy-dioxetane precursor containing a dicyanomethyl chromone acceptor scaffold (NCL) as the US-responsive moiety. After therapeutic US radiation (1 MHz), the singlet oxygen (1O2), as an "intermediary", oxidizes the enol-ether bond of the NCL moiety and then emits NIR light via spontaneous decomposition. Combining the deep penetrability of US with a high signal-to-background ratio of NIR CL, the designed probe PNCL successfully realizes US-activated deep tissue imaging (∼20 mm) and selectively turns on signals in specific tumor foci. Bridging US chemistry with luminescence using an "intermediary" will provide new imaging methods for accurate cancer diagnosis.

A Radio-Pharmaceutical Fluorescent Probe for Synergistic Cancer Radiotherapy and Ratiometric Imaging of Tumor Reactive Oxygen Species.

Radiotherapy (RT) is an effective and widely applied cancer treatment strategy in clinic. However, it usually suffers from radioresistance of tumor cells and severs side effects of excessive radiation dose. Therefore, it is highly significant to improve radiotherapeutic performance and monitor real-time tumor response, achieving precise and safe RT. Herein, an X-ray responsive radio-pharmaceutical molecule containing chemical radiosensitizers of diselenide and nitroimidazole (BBT-IR/Se-MN) is reported. BBT-IR/Se-MN exhibits enhanced radiotherapeutic effect via a multifaceted mechanisms and self-monitoring ROS levels in tumors during RT. Under X-ray irradiation, the diselenide produces high levels of ROS, leading to enhanced DNA damage of cancer cell. Afterwards, the nitroimidazole in the molecule inhibits the damaged DNA repair, offering a synergetic radiosensitization effect of cancer. Moreover, the probe shows low and high NIR-II fluorescence ratios in the absence and presence of ROS, which is suitable for precise and quantitative monitoring of ROS during sensitized RT. The integrated system is successfully applied for radiosensitization and the early prediction of in vitro and in vivo RT efficacy.

Targeted Nanodrugs to Destroy the Tumor Extracellular Matrix Barrier for Improving Drug Delivery and Cancer Therapeutic Efficacy.

One of the main reasons why most cancer patients do not respond well to chemotherapy is that drugs cannot accumulate in tumors at an optimal dose, eventually resulting in failure to prevent cancer cell growth. To improve drug delivery efficiency, we engineered a highly efficient tumor-targeted and stroma-breaking nanocarrier by the modification of iron oxide nanoparticles (IONPs) with a tumor-targeting peptide c(RGDyK) and a hyaluronidase (HAase) on the surface. The yielding nanocomplex, c(RGDyK)-HAase-IONP, targeted the tumor by binding integrin αvß3 and went deeply into the tumors by the degradation of hyaluronic acid (HA), which was highly expressed in the tumor extracellular matrix (ECM). Good biostability and a low pH preferred drug release profile were characterized for c(RGDyK)-HAase-IONP carrying DOX in vitro. c(RGDyK)-HAase-IONP showed an improved tumor-targeting (2.5 times higher) effect after intravenous injection in the MC38 tumor-bearing mice model, as determined by whole-body fluorescence imaging compared to the non-targeted IONPs without HAase. After 5 systemic treatments, c(RGDyK)-HAase-IONP/DOX (5 mg/kg of equivalent dose of DOX) significantly inhibited MC38 tumor growth (22.1 ± 7.4 times relative to the non-treated group). Elevated apoptosis and reduced proliferation in the tumor cell were detected in the c(RGDyK)-HAase-IONP/DOX treated tumors compared to the control groups. Overall, the highly efficient targeted nanocarrier c(RGDyK)-HAase-IONP demonstrated tremendous potency for improving drug delivery and tumor therapy efficacy by targeted degradation of the dense HA barrier in the tumor ECM. We determined that such a tumor stroma-degrading nanosystem was capable of reducing tumor recurrence and drug resistance and could ultimately improve clinical tumor treatment responses.

Hyaluronidase responsive second near-infrared fluorescent nanocomplex for combined HER2 blockade and chemotherapy of HER2+ breast cancer.

The human epidermal growth factor receptor-2-positive (HER2+) type is aggressive and has poor prognosis. Although anti-HER2 therapy alone or in combination with other treatment regimens showed significant improvement in survival outcomes, breast cancer patients are still suffering from tumor relapse and severe dose-limiting side effects. Thus, there is still an unmet challenge to develop effective therapeutic agents for HER2+ breast cancer treatment with minimized side effects. Herein, we produced a stimuli-responsive and tumor-targeted hyaluronic acid (HA) nanocomplex that combined HER2 blockade and chemotherapy for effective HER2+ breast cancer therapy. A hydrophobic NIR-II dye, IR1048, was covalently linked with HA to form a spherical HA-IR1048 nanoparticle (HINP), with Herceptin conjugated on the surface and paclitaxel (PTX) encapsulated inside. The fluorescent signals from the yielding Her-HINP/PTX are quenched originally, but a strong NIR-II signal is generated when HINP is degraded by the hyaluronidase that is overexpressed in breast tumors, thus allowing the tracking and visualization of Herceptin and PTX accumulation. Her-HINP/PTX peaked in HER2+ tumors at 24 h post injection as imaged by NIR-II fluorescent imaging. A significantly improved tumor growth inhibition effect was observed after five systemic treatments compared to single PTX (3.71 ± 0.41 times) or Herceptin (5.98 ± 0.51 times) treatment in a HER2-overexpressed breast cancer mouse model with prolonged survival. Collectively, the designed Her-HINP/PTX presents a new hyaluronidase-responsive and HER2 blockade nanoformulation that can visualize the accumulation of nanocomplexes and release drugs inside tumors for combined HER2+ breast cancer therapy with a great promise for translational study. STATEMENT OF SIGNIFICANCE: The high expressions of a protein called human epidermal growth factor receptor 2 (HER2) in breast tumors make this subtype of cancer aggressive. Currently, chemotherapy combined with a HER2 antibody, Herceptin, is a preferred approach for HER2-positive breast cancer therapy. However, these breast cancer patients still suffer from tumor relapse and severe side effects because various therapeutic agents have inherent different biodistributions, resulting in insufficient treatment effects and unfavorable normal organ uptake of these therapeutic agents. Herein, we produced a nanocomplex carrying both Herceptin and chemotherapy drug to simultaneously deliver two drugs into tumors for efficient HER2+ tumor treatment with minimized side effects, providing new insights for designing a combined therapy strategy.

NIR-II Ratiometric Chemiluminescent/Fluorescent Reporters for Real-Time Monitoring and Evaluating Cancer Photodynamic Therapy Efficacy.

The development of probes for early monitoring tumor therapy response may greatly benefit the promotion of photodynamic therapy (PDT) efficacy. Singlet oxygen (1 O2 ) generation is a typical indicator for evaluating PDT efficacy in cancer. However, most existing probes cannot quantitatively detect 1 O2 in vivo due to the high reactivity and transient state, and thus have a poor correlation with PDT response. Herein, a 1 O2 -responsive theranostic platform comprising thiophene-based small molecule (2SeFT-PEG) and photosensitizer Chlorin e6 (Ce6) micelles for real-time monitoring PDT efficacy is developed. After laser irradiation, the Ce6-produced 1 O2 could simultaneously kill cancer and trigger 2SeFT-PEG to produce increased chemiluminescence (CL) and decreased fluorescence (FL) signals variation at 1050 nm in the second near-infrared (NIR-II, 950-1700 nm) window. Significantly, the ratiometric NIR-II CL/FL imaging at 1050 nm could effectively quantify and monitor the concentration of 1 O2 and O2 consumption or recovery, so as to evaluate the therapeutic efficacy of PDT in vivo. Hence, this 1 O2 activated NIR-II CL/FL probe provides an efficient ratiometric optical imaging platform for real-time evaluating PDT effect and precisely guiding the PDT process in vivo.

In-Situ Assembly of Janus Nanoprobe for Cancer Activated NIR-II Photoacoustic Imaging and Enhanced Photodynamic Therapy.

Inorganic nanoprobes have attracted increasing attention in the biomedical field due to their versatile functionalities and excellent optical properties. However, conventional nanoprobes have a relatively low retention time in the tumor and are mostly applied in the first near-infrared window (NIR-I, 650-950 nm), limiting their applications in accurate and deep tissue imaging. Herein, we develop a Janus nanoprobe, which can undergo tumor microenvironment (TME)-induced aggregation, hence, promoting tumor retention time and providing photoacoustic (PA) imaging in the second NIR (NIR-II, 950-1700 nm) window, and enhancing photodynamic therapy (PDT) effect. Ternary Janus nanoprobe is composed of gold nanorod (AuNR) coated with manganese dioxide (MnO2) and photosensitizer pyropheophorbide-a (Ppa) on two ends of AuNR, respectively, named as MnO2-AuNR-Ppa. In the tumor, MnO2 could be etched by glutathione (GSH) to release Mn2+, which is coordinated with multiple Ppa molecules to induce in situ aggregation of AuNRs. The aggregation of AuNR effectively improves the NIR-II photoacoustic signal in vivo. Moreover, the increased retention time of nanoprobes and GSH reduction in the tumor greatly improve the PDT effect. We believe that this work will inspire further research on specific in situ aggregation of inorganic nanoparticles.

Nanosized Janus AuNR-Pt Motor for Enhancing NIR-II Photoacoustic Imaging of Deep Tumor and Pt2+ Ion-Based Chemotherapy.

Synthetic micro/nanomotors have great potential in deep tissue imaging and in vivo drug delivery because of their active motion ability. However, applying nanomotors with a size less than 100 nm to in vivo imaging and therapy is one of the core changes in this field. Herein, a nanosized hydrogen peroxide (H2O2)-driven Janus gold nanorod-platinum (JAuNR-Pt) nanomotor is developed for enhancing the second near-infrared region (NIR-II) photoacoustic (PA) imaging of deep tissues of tumors and for effective tumor treatment. The JAuNR-Pt nanomotor is prepared by depositing platinum (Pt) on one end of a gold nanorod with varying proportions of Pt shell coverage, including 10%, 25%, 50%, 75%, and 100%. The JAuNR-Pt nanomotor with Pt shell coverage proportions of 50% exhibits the highest diffusion coefficient (De), and it can rapidly move in the presence of H2O2. The self-propulsion of JAuNR-Pt nanomotor enhances cellular uptake, accelerates lysosomal escape, and facilitates continuous release of cytotoxic Pt2+ ions to the nucleus, causing DNA damage and cell apoptosis. The JAuNR-Pt nanomotor presents deep penetration and enhanced accumulation in tumors as well as high tumor treatment effect. Therefore, this work displays deep tumor imaging and an excellent antitumor effect, providing an effective tool for accurate diagnosis and treatment of diseases.

NIR-II Fluorescent Activatable Drug Delivery Nanoplatform for Cancer-Targeted Combined Photodynamic and Chemotherapy.

Nanotheranostics with integrated imaging functions can help monitor nanoparticle accumulation in tumors, thus achieving synergism and higher therapeutic accuracy in cancer therapy. However, it remains challenging to monitor the release of therapeutic drugs in real time from a nanoparticulate drug delivery system (nano-DDS) in the body. Herein, we developed a nano-DDS for fluorescence imaging in the second near-infrared window (NIR-II) region, which can be used for monitoring the responsive release of drugs and cancer-targeted combined photodynamic and chemotherapy. There is a linear correlation between the cumulative release of the drug and the NIR-II fluorescence intensity. Moreover, hyaluronidase/glutathione dual-response RGD-SS-DOX/Ce6@HA-IR-1061 (RSSDCHI) exhibited a higher tumor-to-normal-tissue ratio in NIR-II fluorescence imaging and enhanced antitumor efficacy in vivo. This makes it possible to visualize drug release at the cellular level by the nanocomposites and to predict the treatment effect according to the NIR-II fluorescence intensity in the tumor site, serving as a promising nanoplatform for precision nanomedicine.

Neodymium (3+)-Coordinated Black Phosphorus Quantum Dots with Retrievable NIR/X-Ray Optoelectronic Switching Effect for Anti-Glioblastoma.

Heteroatom interaction of atomically thin nanomaterials enables the improvement of electronic transfer, band structure, and optical properties. Black phosphorus quantum dots (BP QDs) are considered to be candidate diagnostic and/or therapeutic agents due to their innate biocompatibility and exceptional photochemical effects. However, BP QDs are not competitive regarding second near-infrared (NIR-II) window medical diagnosis and X-ray induced phototherapy. Here, an Nd3+ ion coordinated BP QD (BPNd) is synthesized with the aim to sufficiently improve its performances in NIR-II fluorescence imaging and X-ray induced photodynamic therapy, benefitting from the retrievable NIR/X-ray optoelectronic switching effects between BP QD and Nd3+ ion. Given its ultrasmall size and efficient cargo loading capacity, BPNd can easily cross the blood-brain barrier to precisely monitor the growth of glioblastoma through intracranial NIR-II fluorescence imaging and impede its progression by specific X-ray induced, synergistic photodynamic chemotherapy.

In Situ Activatable Ratiometric NIR-II Fluorescence Nanoprobe for Quantitative Detection of H2S in Colon Cancer.

As key characteristic molecules, several H2S-activated probes have been explored for colon cancer studies. However, a few ratiometric fluorescence (FL) probes with NIR-II emissions have been reported for the quantitative detection of H2S in colon cancer in vivo. Here, we developed an in situ H2S-activatable ratiometric nanoprobe with two NIR-II emission signals for the detection of H2S and intelligently lighting up colon cancer. The nanoprobe comprised a down conversion nanoparticle (DCNP), which emitted NIR-II FL at 1550 nm on irradiation with a 980 nm laser (F1550Em, 980Ex). Further, human serum albumin (HSA) was combined with Ag+ on the surface of DCNP to form a DCNP@HSA-Ag+ nanoprobe. In the presence of H2S, Ag2S quantum dots (QDs) were formed in coated HSA, which emitted FL at approximately 1050 nm on irradiation with an 808 nm laser (F1050Em, 808Ex) through an H2S-induced chemical reaction between H2S and Ag+; however, the FL signal of DCNP was stable at 1550 nm (F1550Em, 980Ex), generating a H2S concentration-dependent ratiometric F1050Em, 808Ex/F1550Em, 980Ex signal. The NIR-II ratiometric nanoprobe was successfully used for the accurate quantitative detection of H2S and the detection of the precise location of colon cancer through an endogenous H2S-induced in situ reduction reaction to form Ag2S QDs. Thus, these findings provide a new strategy for the specific detection of targeted molecules and diagnosis of disease based on the in situ-activatable NIR-II ratiometric FL nanoprobe.

NIR-II Photoacoustic Reporter for Biopsy-Free and Real-Time Assessment of Wilson's Disease.

Wilson's disease (WD) is a rare inherited disorder of copper metabolism with pathological copper hyperaccumulation in some vital organs. However, the clinical diagnosis technique of WD is complicated, aggressive, and time-consuming. In this work, a novel ratiometric photoacoustic (PA) imaging nanoprobe in the NIR-II window is developed to achieve noninvasive, rapid, and accurate Cu2+ quantitative detection in vitro and in vivo. The nanoprobe consists of Cu2+ -responsive IR970 dye and a nonresponsive palladium-coated gold nanorod (AuNR-Pd), achieving a concentration-dependent ratiometric PA970 /PA1260 signal change. The urinary Cu2+ content is detectable within minutes down to a detection limit of 76 × 10-9 m. This report acquisition time is several orders of magnitude shorter than those of existing detection approaches requiring complex procedure. Moreover, utilizing the ratiometric PA nanoprobe, PA imaging enables biopsy-free measurement of the liver Cu2+ content and visualization of the liver Cu2+ biodistribution of WD patient, which avoid the body injury during the clinical Cu2+ test using liver biopsy method. The NIR-II ratiometric PA detection method is simple and noninvasive with super precision, celerity, and simplification, which holds great promise as an alternative to liver biopsy for clinical diagnosis of WD.

Plasmonic-Fluorescent Janus Ag/Ag2S Nanoparticles for In Situ H2O2-Activated NIR-II Fluorescence Imaging.

Silver sulfide (Ag2S) has gained widespread attention in second near-infrared (950-1700 nm, NIR-II) window imaging because of its high fluorescence quantum yield and low toxicity. However, its "always on" fluorescence shows inapplicability for targeted molecule-activated biomedical applications. Herein, we first developed a novel silver/silver sulfide Janus nanoparticle (Ag/Ag2S JNP) for specific activatable fluorescence imaging in the NIR-II window. Inner-particle electron compensation from Ag to Ag2S upon laser irradiation endowed JNPs an "off" state of fluorescence, whereas the oxidization of Ag incubated with H2O2, decreasing the electron-transfer effect and illuminating the NIR-II fluorescence of the Ag2S part. In contrast, the absorption of Ag/Ag2S JNPs slightly decreased in an H2O2-dependent manner, showing an activated photoacoustic imaging mechanism. The Ag/Ag2S JNPs were used for noninvasive location and diagnosis of diseases in vivo, such as for liver injury and cancer, with high sensitivity and accuracy.

Quantitative Assessment of Copper(II) in Wilson's Disease Based on Photoacoustic Imaging and Ratiometric Surface-Enhanced Raman Scattering.

Cu2+ is closely related to the occurrence and development of Wilson's disease (WD), and quantitative detection of various copper indicators (especially liver Cu2 and urinary Cu2+) is the key step for the early diagnosis of WD in the clinic. However, the clinic Cu2+ detection approach was mainly based on testing the liver tissue through combined invasive liver biopsy and the ICP-MS method, which is painful for the patient and limited in determining WD status in real-time. Herein, we rationally designed a type of Cu2+-activated nanoprobe based on nanogapped gold nanoparticles (AuNNP) and poly(N-isopropylacrylamide) (PNIPAM) to simultaneously quantify the liver Cu2+ content and urinary Cu2+ in WD by photoacoustic (PA) imaging and ratiometric surface-enhanced Raman scattering (SERS), respectively. In the nanoprobe, one Raman molecule of 2-naphthylthiol (NAT) was placed in the nanogap of AuNNP. PNIPAM and the other Raman molecule mercaptobenzonitrile (MBN) were coated on the AuNNP surface, named AuNNP-NAT@MBN/PNIPAM. Cu2+ can efficiently coordinate with the chelator PNIPAM and lead to aggregation of the nanoprobe, resulting in the absorption red-shift and increased PA performance of the nanoprobe in the NIR-II window. Meanwhile, the SERS signal at 2223 cm-1 of MBN is amplified, while the SERS signal at 1378 cm-1 of NAT remains stable, generating a ratiometric SERS I2223/I1378 signal. Both NIR-II PA1250 nm and SERS I2223/I1378 signals of the nanoprobe show a linear relationship with the concentration of Cu2+. The nanoprobe was successfully applied for in vivo quantitative detection of liver Cu2+ of WD mice through NIR-II PA imaging and accurate quantification of urinary Cu2+ of WD patients by ratiometric SERS. We anticipate that the activatable nanoprobe might be applied for assisting an early, precise diagnosis of WD in the clinic in the future.

Dual Ratiometric SERS and Photoacoustic Core-Satellite Nanoprobe for Quantitatively Visualizing Hydrogen Peroxide in Inflammation and Cancer.

Excessive production of oxidative species alters the normal redox balance and leads to diseases, such as chronic inflammation and cancer. Oxidative species are short-lived species, which makes direct, precise, and real-time measurements difficult. Herein, we report a novel core-satellite gold nanostructure for dual, ratiometric surface-enhanced Raman scattering (SERS) and photoacoustic (PA) imaging to enable the precise detection of inflammation/cancer-related H2 O2 . The combination of H2 O2 -activated second near-infrared (NIR-II) PA imaging and SERS imaging enables the differentiation between the inflamed region and normal tissue with high accuracy. The mesoporous silica shell of the nanoprobe could be used to deliver drugs to the target area to precisely treat disease. Therefore, this core-satellite nanostructure can not only quantitatively and precisely monitor H2 O2 produced in inflammation, tumor, and osteoarthritis in rabbits in real-time, but can also be used to track the progress of the anti-inflammatory treatment in real-time.

A New Class of NIR-II Gold Nanocluster-Based Protein Biolabels for In†Vivo Tumor-Targeted Imaging.

The design of bright NIR-II luminescent nanomaterials that enable efficient labelling of proteins without disturbing their physiological properties in vivo is challenging. We developed an efficient strategy to synthesize bright NIR-II gold nanoclusters (Au NCs) protected by biocompatible cyclodextrin (CD). Leveraging the ultrasmall size of Au NCs (<2 nm) and strong macrocycle-based host-guest chemistry, the as-synthesized CD-Au NCs can readily label proteins/antibodies. Moreover, the labelled proteins/antibodies enable highly efficient in vivo tracking during blood circulation, without disturbing their biodistribution and tumor targeting ability, thus leading to a sensitive tumor-targeted imaging. CD-Au NCs are stable in the harsh biological environment and show good biocompatibility and high renal clearance efficiency. Therefore, the NIR-II biolabels developed in this study provide a promising platform to monitor the physiological behavior of biomolecules in living organisms.

Ag+ -Coupled Black Phosphorus Vesicles with Emerging NIR-II Photoacoustic Imaging Performance for Cancer Immune-Dynamic Therapy and Fast Wound Healing.

A silver-ion-coupled black phosphorus (BP) vesicle (BP Ve-Ag+ ) with a second near infrared (NIR-II) window photoacoustic (PA) imaging capability was firstly constructed to maximize the potential of BP quantum dot (QD) in deeper bioimaging and diversified therapy. The embedded Ag+ could improve the relatively large band gap of BP QD via intense charge coupling based on theoretical simulation results, subsequently leading to the enhanced optical absorption capability, accompanied with the occurrence of the strong NIR-II PA signal. Guiding by NIR-II PA bioimaging, the hidden Ag+ could be precisely released with the disassembly of Ve during photodynamic therapy process and captured by macrophages located in lesion region for arousing synergistic cancer photodynamic/Ag+ immunotherapy. BP Ve-Ag+ can contrapuntally kill pathogenic bacteria and accelerate wound healing monitored by NIR-II PA imaging.