Timely detecting the progression and therapeutic effect of non-alcoholic liver disease is a great challenge due to lacking suitable non-invasive imaging methods. Herein, a novel theranostic nanoplatform based on lanthanide nanorods integrated with photo-triggered NO releasing molecule (NaYF4:Gd/Yb/Er@mSiO2-RBS) is designed for simultaneous diagnosis of liver fibrosis and second near infrared (NIR-II) ratiometric fluorescence imaging of the NO gas-based therapy of liver fibrosis. The mice with liver fibrosis present bright NIR-II emission (1000-1400 nm) via endogenous pigment secreted in liver fibrosis area under 808 nm laser excitation, enabling non-invasive diagnosis of liver fibrosis. In addition, the nanoplatform presents efficient NO gas release for therapy of liver fibrosis and 1532 nm emission activated by 980 nm laser. Importantly, after NO gas therapy, NIR-II fluorescent signal of the endogenous pigment was decreased, while the fluorescent signal around 1532 nm was increased, leading to the specific ratiometric NIR-II imaging of the therapy process with high specificity. Thus, the developed theranostic nanoprobe provided a powerful tool for timely NIR-II ratiometric detecting the progression and therapeutic effect of liver disease.

Bones play vital roles in human health. Noninvasive visualization of the full extent of bones is highly demanded to evaluate many bone-related diseases. Herein, we report poly (acrylic acid) (PAA)-modified NaLuF4:Yb/Er/Gd/Ce@NaYF4 nanoparticles (PAA-Er) with second near-infrared emission beyond 1500 nm (also referred as NIR-IIb) for high-resolution bone/bone marrow imaging and bone fracture diagnosis. The NIR-IIb optical-guided bone marrow imaging presents a high signal to noise ratio, which is superior to that for imaging in the NIR-II window (1000-1400 nm, NIR-IIa). Importantly, we also investigated the size-dependent accumulation of the nanoparticles and the possible accumulation mechanism of the designed PAA-Er nanoprobes in bone marrow. Due to the high affinity capability of the PAA-Er nanoprobes, a highly sensitive NIR-IIb optical-guided bone fracture diagnosis was successfully achieved. This novel technology paves the way to design lanthanide nanoprobes for NIR-IIb optical-guided high-resolution bone marrow imaging and bone-related disease diagnosis.

Gas-based therapy has emerged as a new green therapy strategy for anti-tumor treatment. However, the therapeutic efficacy is still restricted by the deep tissue controlled release, poor lymphocytic infiltration, and inherent immunosuppressive tumor microenvironment (TME). Herein, a new type of nanovaccine is designed by integrating low dose soft X-ray-triggered CO releasing lanthanide scintillator nanoparticles (ScNPs: NaLuF4 :Gd,Tb@NaLuF4 ) with photo-responsive CO releasing moiety (PhotoCORM) for synergistic CO gas/immuno-therapy of tumors. The designed nanovaccine presents significantly boosted radioluminescence and enables deep tissue CO generation at unprecedented tissue depths of 5 cm under soft X-ray irradiation. Intriguingly, CO as a superior immunogenic cell death (ICD) inducer further reverses the deep tissue immunosuppressive TME and concurrently activates adaptive anti-tumor immunity through efficient reactive oxygen species (ROS) generation. More importantly, the designed nanovaccine presents efficient growth inhibition of both local and distant tumors via a soft X-ray activated systemic anti-tumor immunoresponse. This work provides a new strategy of designing anti-tumor nanovaccines for synergistic deep tissue gas-therapy and remote soft X-ray photoactivation of the immune response.

Lanthanide scintillators capable of converting the absorbed X‐ray photon energy to ultraviolet (UV) or visible light, are emerged as promising nanoprobes for multifunctional diagnosis and deep‐tissue antitumor therapy such as X‐ray‐excited fluorescence (XEF) imaging, X‐ray‐triggered photodynamic therapy (X‐PDT), and soft X‐ray‐activated NO gas therapy. Such biomedical tools have the potential to overcome the major challenge of the depth barrier suffered by traditional optics. Recently, various lanthanide scintillators have been designed for diagnosis and therapy of deep‐seated tumors. This minireview presents an overview of recent progress on the lanthanide‐based scintillators and illustration of the potential challenges and future development.

Combining photodynamic therapy (PDT) and immunotherapy has shown profound impact for synergistic treatment of malignant tumors. However, the shallow penetration depth of the traditional visible light activated PDT, immunosuppressive tumor microenvironment (TME), and poor immunogenicity of deep‐seated solid tumors have significantly impeded the therapeutic efficiency. Herein, a soft X‐ray activated nanoprobe is rationally engineered via integrating porphyrin Zr‐based metal–organic framework with lanthanide NaYF 4 :Gd,Tb@NaYF 4 scintillator nanoparticles (SNPs) by a new in situ growth strategy for synergistic PDT and immunotherapy of tumor. The nanoprobe possesses remarkably enhanced reactive oxygen species (ROS) generation triggered by soft X‐ray via further covalently grafting rose bengal on the nanoprobe, even at tissue depths of 3 cm. Moreover, the soft X‐ray induced ROS can act as potential immunogenic cell death (ICD) trigger, subsequently leading to the activation of the adaptive antitumor immune‐response. Significantly, the boosted ROS generation can further modulate the immunosuppressive TME. This work provides new strategy of designing antitumor nanoprobes for soft X‐ray triggered deep‐tissue PDT and immune response, breaking the depth barriers suffered by the traditional photoactivated PDT or ICD using visible and near infrared light.

Metformin as a hypoglycemic drug for antidiabetic treatment has emerged as a multipotential drug for many disease treatments such as cognitive disorders, cancers, promoting weight loss. However, overdose uptake may upregulate the hepatic H2S level, subsequently leading to serious liver injury and toxicity. Therefore, developing intelligent second near-infrared (NIR-II) emitting nanoprobes by using endogenous H2S as a smart trigger for noninvasive highly specific in situ monitoring of the metformin-induced hepatotoxicity is highly desirable, which is rarely explored. Herein, an endogenous H2S activated orthogonal NIR-II emitting myrica rubra-like nanoprobe based on NaYF4:Gd/Yb/Er@NaYF4:Yb@SiO2 coated with Ag nanodots was explored for highly specific in vivo ratiometrically monitoring of hepatotoxicity. The designed nanoprobes were mainly uptaken by the liver and subsequently converted to NaYF4:Gd/Yb/Er@NaYF4:Yb@SiO2@Ag2S via in situ sulfuration reaction triggered by the overexpressed endogenous H2S in the injured liver tissues, finally leading to a turn-on orthogonal emission centered at 1053 nm (irradiation by 808 nm laser) and 1525 nm (irradiation by 980 nm laser). The designed nanoprobe presents a high detection limit down to 0.7 nM of H2S. More importantly, the in situ highly specific ratiometric imaging of the metformin-induced hepatotoxicity was successfully achieved by using the activatable orthogonal NIR-II emitting probe. Our results provide an NIR-II ratiometric fluorescence imaging strategy for highly sensitive/specific diagnosis of hepatotoxicity levels induced by metformin.

An endogenous H2S-triggered intelligent optical nanoprobe combining second near-infrared (NIR-II) fluorescence with photoacoustic (PA) imaging can provide more comprehensive information to further improve the sensitivity and reliability of diagnosis for colorectal tumor, which is rarely explored. Herein, an endogenous H2S-triggered SiO2@Ag nanoprobe was designed for in situ dual-modal NIR-II/PA imaging of colorectal cancer. The designed dual-modal nanoprobe can be converted to SiO2@Ag2S after in situ biosynthesis via a sulfuration reaction with the over-expressed endogenous H2S in the colorectal tumor. More importantly, the designed SiO2@Ag nanoprobe exhibits high sensitivity and specificity for diagnosing colorectal cancer in vivo via dual-modal NIR-II/PA imaging. These results provide a new NIR-II/PA dual-modal imaging strategy for noninvasive intelligent detection of colorectal cancer.

Lanthanide based nanoprobe with high efficient down-shifting second near-infrared (NIR-II, 1000-1700 nm) emission has emerged as a promising agent for tumor-associated vascular visualization. However, most of the developed lanthanide-based NIR-II-emissive probes are activated by 980 nm laser, leading to the concern of biological overheating effect. Herein, the high quality 808 nm laser activated NaYF4:Gd/Yb/Er/Nd/Ce@NaYF4:Nd core-shell nanoprobes with significantly improved NIR-II emission beyond 1500 nm and eliminated overheating effect were developed for imaging-guided resection surgery of tumor and vascular visualization. Methods: The core-shell nanoprobe with boosted NIR-II emission and eliminated heating effect was achieved with combination of Nd-sensitizing and Ce-doping strategies. The NIR-II optical imaging and toxicity assessment were demonstrated by in vivo and in vitro experiments. Results: The designed core-shell nanoprobe presented superior NIR-II emission beyond 1500 nm than the core only nanoparticle and NIR-II emission intensity was improved up to 11.0 times by further suppressing the upconversion (UC) pathway through doping Ce3+. More importantly, non-invasive tumor vascular imaging and NIR-II optical imaging-guided surgical resection of tumor were successfully achieved. Conclusion: It is expected that the Nd-sensitized lanthanide-based nanoprobe with significant improvement in NIR-II emission and eliminated overheating effect is a highly promising probe for NIR-II imaging, making it more competitive in non-invasive vascular imaging and imaging-guided tumor resection surgery.

A soft X-ray activated scintillator-based light transducer for controllable NO release was developed for gas-sensitized in vivo tumor therapy.

Nitric oxide (NO)-based gas therapy is emerged as a new adjunct anti-tumor treatment method, which has triggered a great research interest. Nevertheless, due to the short half-life of NO gas in vivo, it is of significance to develop NO-gas based gasotransmitter with controllable NO release for deep-tissue anti-tumor therapy. Herein, a novel soft X-ray activated persistent luminescence nanotransducer is designed for controllable and long-lasting NO release and deep-tissue anti-cancer therapy by integrating ZnGa2O4:Mn (ZGO:Mn) nanoparticles with light-responsive NO donor (RBS). With the merits of the ultra-low dosage (down to 0.9 mGy) soft X-ray activated persistent luminescence from small sized ZGO:Mn, continuous NO release is achieved for about 40 min after stopping the irradiation of X-ray. Moreover, the green persistent luminescence can be renewably activated by in-situ soft X-ray irradiation, leading to the repeatable long-lasting NO release in deep tissue (up to 24 mm). And the designed NO-releasing platform presents efficient in vitro and in vivo anti-cancer therapy. Therefore, the designed persistent luminescence-based NO gasotransmitter provides a new NO-releasing strategy for depth-independent gas-sensitized therapeutic applications.

Silk fibroin-based materials spun by silkworms present excellent biocompatible and biodegradable properties, endowing them with broad applications for use in in vivo implanted devices. Therefore, it is highly desirable to explore functionalized silk with additional optical bioimaging abilities for the direct in situ monitoring of the status of implanted devices in vivo. Herein, a new type of silk material with a second near-infrared (NIR-II, 1000-1700 nm) emission is explored for the real-time observation of a biological stent model using a general route of feeding larval silkworms with lanthanide-based NaYF4:Gd3+/Yb3+/Er3+@SiO2 nanocrystals. After being fed lanthanide nanocrystals, the silk spun by silkworms shows efficient NIR-II emission beyond 1500 nm. Moreover, NIR-II bio-imaging guided biological stent model monitoring presents a superior signal-to-noise (S/N) ratio compared to the traditional optical imaging by utilizing the upconversion (UC) region. These findings open up the possibility of designing NIR-II optically functionalized silk materials for highly sensitive and deep-tissue monitoring of the in vivo states of the implanted devices.

Gaseous therapy based on nitric oxide (NO) has emerged as a potential tumor therapy route. However, the development of a NO generator with precisely controlled NO releasing in the target site is still facing enormous challenges. Herein, a typical NO delivery platform by integrating the hollow structured polydopamine (PDA) coated Bi2S3 nanohybrids (denoted as H-Bi2S3@PDA) with a heat-sensitive S-nitrosothiol (RSNO) molecule was explored for near-infrared (NIR) light-responsive on-demand NO-releasing and synergetic gas/photothermal combination therapy of tumors. The designed H-Bi2S3@PDA nanocomposites hold high photothermal conversion efficiency of 46.13% under irradiation of a NIR laser, leading to NIR light-triggered controllable generation of NO gas via breaking the S-NO bonds of the heat-sensitive RSNO molecules. More importantly, synergistic gas/photothermal therapy of the tumor was also achieved, which presented remarkable inhibition growth and ablation of tumors. These findings provide the opportunity to design a NIR light-activated NO generator with a combination of photothermal materials and heat-sensitive molecules for integrative gas/photothermal therapy in deep tumors.

The optical imaging guided tumor vessels and vascular malformation visualization by using the second near infrared emission beyond 1500 nm (NIR-II) is emerged as the next generation fluorescence imaging technique for early tumor diagnosis and identification of tumor-associated vascular features. On the other hand, developing theranostic probes for NIR-II imaging guided photothermal therapy (PTT) is of great significance, which is rarely explored. Herein, a high performance theranostic nanoplatform based on the core-shell structured NaLuF4 nanorods@polydopamine (denoted as NRs@PDA) by integrating the new advanced NIR-II imaging beyond 1500 nm with PTT function was developed for tumor-associated vascular malformation visualization and imaging-guided PTT. Methods: In this work, the hydrophilic NaLuF4 NRs@PDA therapeutic probe was synthesized by using a reverse microemulsion method. The crystal phase, morphology, emission spectra and photothermal performance of the synthesized samples were systematically characterized. The NIR-II optical imaging and photothermal properties were investigated by in vitro and in vivo experiments. Results: The NaLuF4 NRs@PDA therapeutic probe possessed efficient NIR-II emission centered at 1525 nm with high quantum yield (QY), good photo-stability and high biocompatibility. In vivo NIR-IIb imaging based on the designed probe can clearly visualize the whole-body vessel and brain vessel with high spatial resolution, especially tumor-associated vessels. In addition, in vitro and in vivo experiments also demonstrated that the designed NaLuF4 NRs@PDA probe possessed efficient photothermal conversion efficiency (40.18%) for PTT ablation of tumor. Conclusion: With the excellent NIR-II imaging ability and PTT of tumor, the designed theranostic nanoplatform successfully realize the simultaneous tumor vessel diagnosis and tumor therapy, which may provide the opportunity of designing new theranostic bioprobes with combination of the NIR-II optical imaging technique and PTT function for tumor diagnosis and therapy.

Overexpression of endogenous H2S is one of the key characteristic in colon cancer. However, developing endogenous H2S-activated optical probes for specific diagnosis of colorectal cancer is rarely explored. Herein, an in situ H2S-activatable second near-infrared (NIR-II)-emitting nanoprobe based on Ag-chicken egg white (Ag-CEW) complex for intelligently lighting up colorectal cancer was explored. The designed Ag-CEW complex holds efficient NIR-II emission of 1,000-1,400 nm via endogenous H2S-induced in situ chemical reaction to form Ag2S quantum dots (QDs). After reaction, the designed Ag-CEW complex with high photo-stability and biocompatibility was successfully used for NIR-II imaging-guided specific visualization and precise location of colorectal cancer via endogenous H2S activation. Therefore, our findings provide a new route for specifically targeting diagnosis of colon cancer based on the in situ-activatable NIR-II probe.

Optical bioimaging in second near-infrared window (NIR-II, 1000-1700 nm) has been emerged as an indispensable tool for highly sensitive disease detection. In this work, intense NIR-II emissive polyacrylic acid (PAA) modified NaLuF4: Gd/Nd nanorods (PAA-NRs) with pure hexagonal phase and uniform size were explored for high sensitivity in vivo NIR-II bioimaging and optical imaging-guided small tumor detection. The NIR-II emission of the NaLuF4: Gd host can be readily adjusted by doping Nd3+, making it promising emission centered at 1056 nm and 1328 nm with high photo-stability. The time-dependent in vivo tracking results validate that the PAA-NRs are mainly accumulated in the reticuloendothelial system (RES) and excreted through the hepatic pathway. In addition, NIR-II optical imaging-guided small tumor (down to 5 mm) diagnosis was successfully achieved. Remarkably, in vivo small blood vessel with high spatial resolution (~105 μm) was detected clearly. And the histological tests reveal that our designed hydrophilic NRs present negligible toxicity effects and good biocompatibility in living animals. Besides the NIR-II emission, the PAA-NRs also present X-ray absorption features for X-ray bioimaging. These findings demonstrate that the explored lanthanide-based NRs with controllable size, efficient NIR-II emission and decent biocompatibility are promising NIR-II contrast agents for future biomedical applications, such as, early diagnosis of small tumor, vascular related disease imaging and angiogenesis diagnosis.

Theranostic nanoprobes with a combination of highly sensitive optical bioimaging and photothermal therapy (PTT) are considered advanced tools for improving the detection precision and the imaging‐guided hyperthermal therapy efficacy against tumor in the biomedical area. Compared with the traditional visible/first near‐infrared (NIR‐I, 650–900 nm) light‐emitting optical probe, a nanoprobe capable of generating the second near‐infrared (NIR‐II, 1000–1700 nm) emission is emerging as the next‐generation optical imaging technique with high‐sensitivity, and high spatial/time resolution owing to its remarkably reduced photon scattering losses. However, a multifunctional theranostic nanoplatform incorporated with the new advanced NIR‐II optical imaging and PTT has not yet been explored. Herein, a general strategy for designing theranostic nanoplatforms by integrating NIR‐II optical bioimaging with photothermal functions via in situ growth of Cu 2− x S quantum dots on the lanthanide nanorods is demonstrated. The as‐prepared NaLnF 4 :Yb/Er@Cu 2− x S hybrid nanoprobes with a core‐satellite structure present excellent NIR‐II emission centered at 1525 nm, highly stable photothermal effects and good biocompatibility. These designed theranostic nanoprobes are utilized for NIR‐II optical imaging, small tumor detection (5 mm in diameter), and PTT. More importantly, non‐invasive brain vessel visualization with high spatial resolution (44.2 µm) through scalp and skull without craniotomy is demonstrated. Therefore, these results pave the way to designing new multifunction theranostic nanoplatforms for highly sensitive NIR‐II optical‐guided tumor detection, non‐invasive blood vessel imaging, and PTT.

In article number 1800153, Songjun Zeng, Jianhua Hao and co-workers demonstrate a general in-situ growth strategy for designing integrative NaLnF4@Cu2-xS theranostic nanoprobes with a combination of efficient NIR-II emission and high performance photothermal therapy (PTT). NIR-II Optical imaging guided small tumor detection, non-invasive in vivo brain vessel imaging and PTT of tumors are achieved, providing a new opportunity for designing highly sensitive theranostic nanoprobes by integrating NIR-II imaging with PTT.

The optical probes working in the second near-infrared (NIR-II) window have attracted increasing research interest for their advantages of high tissue penetration depth, low autofluorescence, and unprecedentedly improved imaging sensitivity and spatial resolution. Therefore, it is of great significance to design a new nanoplatform by integration of NIR-II optical imaging and drug delivery functions. Herein, a multifunctional nanoplatform based on GdPO4:Nd 3+ yolk–shell sphere was developed for dual-modal in vivo NIR-II/X-ray bioimaging and pH-responsive drug delivery. The in vivo NIR-II bioimaging and realtime tracking presented that these probes were mainly accumulated in liver and spleen. Moreover, owing to the large X-ray absorption coefficient of Gd, these probes are successfully used as superior X-ray imaging agents than iobitridol. The in vivo toxicity assessments demonstrate the low biotoxicity of the GdPO4:Nd 3+ spheres in living animals. More importantly, apart from the excellent dual-modal bioimaging, these yolk–shell-structured probes were also used as ideal nanotransducer for pHresponsive drug delivery of doxorubicin (DOX). These findings open up the opportunity of designing theranostic nanoplatform with integration of imaging-based diagnosis and therapy.

In vivo optical imaging by using a new imaging window located at short-wavelength infrared region (1000-1700 nm, named as NIR II) presents an unprecedented improvement in imaging sensitivity and spatial resolution over the traditional visible and near-infrared light. However, the most developed NIR II-emitters are hardly excreted from live animals, leading to unknown long-term toxicity concerns, which hinder the widespread applications of this advanced imaging technology. Here, we developed a new generation molecular NIR II-emitting probe based on Nd-diethylene triamine pentacetate acid (DTPA) complex. The designed molecular Nd-DTPA probe with bright narrow band emission at 1330 nm is successfully used for highly sensitive in vivo NIR II bioimaging with rapid renal excretion, high biocompatibility and optical-guided tiny tumor (down to ∼3 mm) detection for the first time. Moreover, the Nd-DPTA complex also holds great promise as an X-ray contrast agent. These findings open up the possibility for designing a new generation of multi-modal small molecular probe for early tumor diagnosis and favor the clinic translation of the advanced NIR II imaging method.

Optical bioimaging that works in the second near infrared region (NIR-II, 1000-1700 nm) has emerged as a next generation imaging technique with superior imaging sensitivity and spatial resolution compared to traditional optical imaging utilizing visible and near-infrared lights (below 900 nm). Herein, a new Sc-based NIR-II probe was explored for high performance NIR-II in vivo bioimaging and optical imaging-guided non-invasive brain blood vessel visualization. The lanthanide doped Sc-based probes (KSc2F7:Yb3+/Er3+) possess a pure orthorhombic phase structure with size control by adjusting the F- ion content. These probes present a dominant red upconversion (UC) emission, which is significantly different from the traditional NaYF4:Yb/Er host, which usually has a green UC emission. More importantly, apart from the dominant red UC emission, these probes also possess a strong NIR-II downconversion (DC) emission centered at 1525 nm, which is usually ignored for bioimaging applications. In vivo NIR-II imaging reveals that our explored Sc-based nanorods are promising probes for highly sensitive optical imaging. Moreover, non-invasive through-skull fluorescence bioimaging of brain vessels with high spatial resolution was demonstrated. Therefore, it is expected that Sc-based nanomaterials with unique dominant red UC and DC NIR-II emissions beyond 1500 nm are ideal probes for bio-applications.