Recent Progress on Tumor Microenvironment-Activated NIR-II Phototheranostic Agents with Simultaneous Activation for Diagnosis and Treatment.

Malignant tumors seriously threaten human life and well-being. Emerging Near-infrared II (NIR-II, 1000-1700 nm) phototheranostic nanotechnology integrates diagnostic and treatment modalities, offering merits including improved tissue penetration and enhanced spatiotemporal resolution. This remarkable progress has opened promising avenues for advancing tumor theranostic research. The tumor microenvironment (TME) differs from normal tissues, exhibiting distinct attributes such as hypoxia, acidosis, overexpressed hydrogen peroxide, excess glutathione, and other factors. Capitalizing on these attributes, researchers have developed TME-activatable NIR-II phototheranostic agents with diagnostic and therapeutic attributes concurrently. Therefore, developing TME-activatable NIR-II phototheranostic agents with diagnostic and therapeutic activation holds significant research importance. Currently, research on TME-activatable NIR-II phototheranostic agents is still in its preliminary stages. This review examines the recent advances in developing dual-functional NIR-II activatable phototheranostic agents over the past years. It systematically presents NIR-II phototheranostic agents activated by various TME factors such as acidity (pH), hydrogen peroxide (H2 O2 ), glutathione (GSH), hydrogen sulfide (H2 S), enzymes, and their hybrid. This encompasses NIR-II fluorescence and photoacoustic imaging diagnostics, along with therapeutic modalities, including photothermal, photodynamic, chemodynamic, and gas therapies triggered by these TME factors. Lastly, the difficulties and opportunities confronting NIR-II activatable phototheranostic agents in the simultaneous diagnosis and treatment field are highlighted.

PdMo bimetallene nanozymes for photothermally enhanced antibacterial therapy and accelerated wound healing.

Although antibacterial platforms involving nanozymes have been extensively investigated, there are still problems of poor reactive oxygen species generation efficiency and obstinate bacterial biofilms. Developing a nanozyme-photothermal therapy nanoplatform with superior sterilization effects and minimal side effects would be a good alternative for completely eliminating bacteria and biofilms. Herein, an ultrathin PdMo bimetallene nanozyme with a planar topology and boosted metal utilization, exhibiting excellent photothermal and peroxidase-like activity, is designed for synergistic nanozyme-photothermal sterilization applications and accelerated wound healing. The superior catalytic activity of PdMo bimetallene nanozymes could convert a biosafe concentration of hydrogen peroxide (H2O2) into large quantities of toxic hydroxyl radicals (•OH) under laser irradiation, enhancing bacterial membrane permeability and thermal sensitivity for efficient removal of bacteria and biofilms. In addition, PdMo bimetallene presents a good wound-healing ability according to the results of fibroblast proliferation and collagen deposition with minor side effects. This work would provide an innovative avenue for developing metallene-based nanozymes for biomedical applications.

Recent Advances on NIR-II Light-Enhanced Chemodynamic Therapy.

Chemodynamic therapy (CDT) is a particular oncological therapeutic strategy by generates the highly toxic hydroxyl radical (•OH) from the dismutation of endogenous hydrogen peroxide (H2O2) via Fenton or Fenton-like reactions. However, single CDT therapies have been limited by unsatisfactory efficacy. Enhanced chemodynamic therapy (ECDT) triggered by near-infrared (NIR) is a novel therapeutic modality based on light energy to improve the efficiency of Fenton or Fenton-like reactions. However, the limited penetration and imaging capability of the visible (400-650 nm) and traditional NIR-I region (650-900 nm) light-amplified CDT restrict the prospects for its clinical application. Combined with the high penetration/high precision imaging characteristics of the second near-infrared (NIR-II,) nanoplatform, it is expected to kill deep tumors efficiently while imaging the treatment process in real-time, and more notably, the NIR-II region radiation with wavelengths above 1000 nm can minimize the irradiation damage to normal tissues. Such NIR-II ECDT nanoplatforms have greatly improved the effectiveness of CDT therapy and demonstrated extraordinary potential for clinical applications. Accordingly, various strategies have been explored in the past years to improve the efficiency of NIR-II Enhanced CDT. In this review, the mechanisms and strategies used to improve the performance of NIR-II-enhanced CDT are outlined.

Rational design of NIR-II molecule-engineered nanoplatform for preoperative downstaging and imaging-guided surgery of orthotopic hepatic tumor.

Orthotopic advanced hepatic tumor resection without precise location and preoperative downstaging may cause clinical postoperative recurrence and metastasis. Early accurate monitoring and tumor size reduction based on the multifunctional diagnostic-therapeutic integration platform could improve real-time imaging-guided resection efficacy. Here, a Near-Infrared II/Photoacoustic Imaging/Magnetic Resonance Imaging (NIR-II/PAI/MRI) organic nanoplatform IRFEP-FA-DOTA-Gd (IFDG) is developed for integrated diagnosis and treatment of orthotopic hepatic tumor. The IFDG is designed rationally based on the core "S-D-A-D-S" NIR-II probe IRFEP modified with folic acid (FA) for active tumor targeting and Gd-DOTA agent for MR imaging. The IFDG exhibits several advantages, including efficient tumor tissue accumulation, good tumor margin imaging effect, and excellent photothermal conversion effect. Therefore, the IFDG could realize accurate long-term monitoring and photothermal therapy non-invasively of the hepatic tumor to reduce its size. Next, the complete resection of the hepatic tumor in situ lesions could be realized by the intraoperative real-time NIR-II imaging guidance. Notably, the preoperative downstaging strategy is confirmed to lower the postoperative recurrence rate of the liver cancer patients under middle and advanced stage effectively with fewer side effects. Overall, the designed nanoplatform demonstrates great potential as a diagnostic-therapeutic integration platform for precise imaging-guided surgical navigation of orthotopic hepatic tumors with a low recurrence rate after surgery, providing a paradigm for diagnosing and treating the advanced tumors in the future clinical translation application.

Tumor Microenvironment-Responsive One-for-All Molecular-Engineered Nanoplatform Enables NIR-II Fluorescence Imaging-Guided Combinational Cancer Therapy.

The activable NIR-based phototheranostic nanoplatform (NP) is considered an efficient and reliable tumor treatment due to its strong targeting ability, flexible controllability, minimal side effects, and ideal therapeutic effect. This work describes the rational design of a second near-infrared (NIR-II) fluorescence imaging-guided organic phototheranostic NP (FTEP-TBFc NP). The molecular-engineered phototheranostic NP has a sensitive response to glutathione (GSH), generating hydrogen sulfide (H2S) gas, and delivering ferrocene molecules in the tumor microenvironment (TME). Under 808 nm irradiation, FTEP-TBFc could not only simultaneously generate fluorescence, heat, and singlet oxygen but also greatly enhance the generation of reactive oxygen species to improve chemodynamic therapy (CDT) and photodynamic therapy (PDT) at a biosafe laser power of 0.33 W/cm2. H2S inhibits the activity of catalase and cytochrome c oxidase (COX IV) to cause the enhancement of CDT and hypothermal photothermal therapy (HPTT). Moreover, the decreased intracellular GSH concentration further increases CDT's efficacy and downregulates glutathione peroxidase 4 (GPX4) for the accumulation of lipid hydroperoxides, thus causing the ferroptosis process. Collectively, FTEP-TBFc NPs show great potential as a versatile and efficient NP for specific tumor imaging-guided multimodal cancer therapy. This unique strategy provides new perspectives and methods for designing and applying activable biomedical phototheranostics.

Trisulfide Bond-Mediated Molecular Phototheranostic Platform for "Activatable" NIR-II Imaging-Guided Enhanced Gas/Chemo-Hypothermal Photothermal Therapy.

Tumor microenvironment (TME)-triggered phototheranostic platform offers a feasible strategy to improve cancer diagnosis accuracy and minimize treatment side effects. Developing a stable and biocompatible molecular phototheranostic platform for TME-activated second near-infrared (NIR-II) fluorescence imaging-guided multimodal cascade therapy is a promising strategy for creating desirable anticancer agents. Herein, a new NIR-II fluorescence imaging-guided activatable molecular phototheranostic platform (IR-FEP-RGD-S-S-S-Fc) is presented for actively targeted tumor imaging and hydrogen sulfide (H2 S) gas-enhanced chemodynamic-hypothermal photothermal combined therapy (CDT/HPTT). It is revealed for the first time that the coupling distance between IR-FE and ferrocene is proportional to the photoinduced electron transfer (PET), and the aqueous environment is favorable for PET generation. The part of Cyclic-RGDfK (cRGDfk) peptides can target the tumor and benefit the endocytosis of nanoparticles. The high-concentration glutathione (GSH) in the TME will separate the fluorescence molecule and ferrocene by the GSH-sensitive trisulfide bond, realizing light-up NIR-II fluorescence imaging and a cascade of trimodal synergistic CDT/HPTT/gas therapy (GT). In addition, the accumulation of hydroxyl radicals (•OH) and down-regulation of glutathione peroxidase 4 (GPX4) can produce excessive harmful lipid hydroperoxides, ultimately leading to ferroptosis.

CT radiomics model for predicting the Ki-67 proliferation index of pure-solid non-small cell lung cancer: a multicenter study.

Purpose: This study aimed to explore the efficacy of the computed tomography (CT) radiomics model for predicting the Ki-67 proliferation index (PI) of pure-solid non-small cell lung cancer (NSCLC). Materials and methods: This retrospective study included pure-solid NSCLC patients from five centers. The radiomics features were extracted from thin-slice, non-enhanced CT images of the chest. The minimum redundancy maximum relevance (mRMR) and least absolute shrinkage and selection operator (LASSO) were used to reduce and select radiomics features. Logistic regression analysis was employed to build predictive models to determine Ki-67-high and Ki-67-low expression levels. Three prediction models were established: the clinical model, the radiomics model, and the nomogram model combining the radiomics signature and clinical features. The prediction efficiency of different models was evaluated using the area under the curve (AUC). Results: A total of 211 NSCLC patients with pure-solid nodules or masses were included in the study (N=117 for the training cohort, N=49 for the internal validation cohort, and N=45 for the external validation cohort). The AUC values for the clinical models in the training, internal validation, and external validation cohorts were 0.73 (95% CI: 0.64-0.82), 0.75 (95% CI:0.62-0.89), and 0.72 (95% CI: 0.57-0.86), respectively. The radiomics models showed good predictive ability in diagnosing Ki-67 expression levels in the training cohort (AUC, 0.81 [95% CI: 0.73-0.89]), internal validation cohort (AUC, 0.81 [95% CI: 0.69-0.93]) and external validation cohort (AUC, 0.78 [95% CI: 0.64-0.91]). Compared to the clinical and radiomics models, the nomogram combining both radiomics signatures and clinical features had relatively better diagnostic performance in all three cohorts, with the AUC of 0.83 (95% CI: 0.76-0.90), 0.83 (95% CI: 0.71-0.94), and 0.81 (95% CI: 0.68-0.93), respectively. Conclusion: The nomogram combining the radiomics signature and clinical features may be a potential non-invasive method for predicting Ki-67 expression levels in patients with pure-solid NSCLC.

The First-in-Human Whole-Body Dynamic Pharmacokinetics Study of Aptamer.

Serving as targeting ligands, aptamers have shown promise in precision medicine. However, the lack of knowledge of the biosafety and metabolism patterns in the human body largely impeded aptamers' clinical translation. To bridge this gap, here we report the first-in-human pharmacokinetics study of protein tyrosine kinase 7 targeted SGC8 aptamer via in vivo PET tracking of gallium-68 (68Ga) radiolabeled aptamers. The specificity and binding affinity of a radiolabeled aptamer, named 68Ga[Ga]-NOTA-SGC8, were maintained as proven in vitro. Further preclinical biosafety and biodistribution evaluation confirmed that aptamers have no biotoxicity, potential mutation risks, or genotoxicity at high dosage (40 mg/kg). Based on this result, a first-in-human clinical trial was approved and carried out to evaluate the circulation and metabolism profiles, as well as biosafety, of the radiolabeled SGC8 aptamer in the human body. Taking advantage of the cutting-edge total-body PET, the aptamers' distribution pattern in the human body was acquired in a dynamic fashion. This study revealed that radiolabeled aptamers are harmless to normal organs and most of them are accumulated in the kidney and cleared from the bladder via urine, which agrees with preclinical studies. Meanwhile, a physiologically based pharmacokinetic model of aptamer was developed, which could potentially predict therapeutic responses and plan personalized treatment strategies. This research studied the biosafety and dynamic pharmacokinetics of aptamers in the human body for the first time, as well as demonstrated the capability of novel molecular imaging fashion in drug development.

NIR-II Imaging-Guided Mitochondrial-Targeting Organic Nanoparticles for Multimodal Synergistic Tumor Therapy.

Effectively interfering energy metabolism in tumor cells and simultaneously activating the in vivo immune system to perform immune attacks are meaningful for tumor treatment. However, precisely targeted therapy is still a huge challenge. Herein, a mitochondrial-targeting phototheranostic system, FE-T nanoparticles (FE-T NPs) are developed to damage mitochondria in tumor cells and change the tumor immunosuppressive microenvironment. FE-T NPs are engineered by encapsulating the near-infrared (NIR) absorbed photosensitizer IR-FE-TPP within amphiphilic copolymer DSPE-SS-PEG-COOH for high-performing with simultaneous mitochondrial-targeting, near-infrared II (NIR-II) fluorescence imaging, and synchronous photothermal therapy (PTT) /photodynamic therapy (PDT) /immune therapy (IMT). In tumor treatment, the disulfide in the copolymer can be cleaved by excess intracellular glutathione (GSH) to release IR-FE-TPP and accumulate in mitochondria. After 808 nm irradiation, the mitochondrial localization of FE-T NPs generated reactive oxygen species (ROS), and hyperthermia, leading to mitochondrial dysfunction, photoinductive apoptosis, and immunogenic cell death (ICD). Notably, in situ enhanced PDT/PTT in vivo via mitochondrial-targeting with FE-T NPs boosts highly efficient ICD toward excellent antitumor immune response. FE-T NPs provide an effective mitochondrial-targeting phototheranostic nanoplatform for imaging-guided tumor therapy.

Magnetic RuCo aerogels with enhanced peroxidase-like activity by regulation of boron and oxygen vacancies for colorimetric biosensing applications.

Metallic aerogels (MAs) are self-supported porous nanomaterials with excellent catalytic activity, which could be a promising candidate for high-performance nanozymes. The interface regulation by heteroatom and vacancies is an effective strategy for boosting the enzyme-mimicking activity. Herein, magnetic RuCo aerogels with doping of boron and oxygen vacancies were prepared by a one-pot spontaneous NaBH4 gelation method under a low temperature. The three-dimensional network structure with high specific surface area and interlinked pores of RuCo aerogels afford abundant active sites to facilitate the interaction with substrates. Moreover, the monolithic structure avoided conventional aggregation, thus enhancing stability during catalysis. Introducing elemtal boron and oxygen vacancies adjusted the electronic structure of RuCo aerogels to achieve enhanced enzyme-like performances. It is found that the RuCo aerogel nanozyme can mimic nature peroxidase, demonstrating their viable applications in the bioassay of H2O2 and glucose. The constructed glucose sensor possesses acceptable sensitivity and stability with a linear range of 0.002 ~ 5 mM and a low detection limit (1.66 µM). This work provides insights into the rational design of advanced nanozymes and paves the avenue for the applications of metallic aerogels in the bioassay field. A boron-doped RuCo bimetallic aerogel with rich oxygen vacancies was prepared by a facile self-assembly method under an ice bath. The unique physical and electronic structure of RuCo aerogel results in the improvement of the intrinsic peroxidaselike activity, and thus, a sensitive and robust colorimetric glucose sensor could be developed.

Clearance pathways of near-infrared-II contrast agents.

Near-infrared-II (NIR-II) bioimaging gradually becomes a vital visualization modality in the real-time investigation for fundamental biological research and clinical applications. The favorable NIR-II contrast agents are vital in NIR-II imaging technology for clinical translation, which demands good optical properties and biocompatibility. Nevertheless, most NIR-II contrast agents cannot be applied to clinical translation due to the acute or chronic toxicity caused by organ retention in vivo imaging. Therefore, it is critical to understand the pharmacokinetic properties and optimize the clearance pathways of NIR-II contrast agents in vivo to minimize toxicity by decreasing organ retention. In this review, the clearance mechanisms of biomaterials, including renal clearance, hepatobiliary clearance, and mononuclear phagocytic system (MPS) clearance, are synthetically discussed. The clearance pathways of NIR-II contrast agents (classified as inorganic, organic, and other complex materials) are highlighted. Successively analyzing each contrast agent barrier, this review guides further development of the clearable and biocompatible NIR-II contrast agents.

A mitochondria-targeted molecular phototheranostic platform for NIR-II imaging-guided synergistic photothermal/photodynamic/immune therapy.

Phototherapy is a conducive and non-invasive strategy for cancer therapy under light irradiation. Inspiringly, fluorescence imaging in the second near-infrared window (NIR-II, 1000-1700 nm) holds a great promise for imaging-guided phototherapy with deep penetration and high spatiotemporal resolution. However, most phototherapeutics still face great challenges, including complicated synthesis of agents, potential biotoxicity and unsatisfied therapeutic outcomes. Herein, a near-infrared laser triggered molecular photosensitizer FEPT, modified with triphenylphosphine PEGylation (PEG2000-TPP), is developed for NIR-II imaging-guided mitochondria-targeting synergistic photothermal therapy (PTT)/photodynamic therapy (PDT)/immune therapy (IMT). The mitochondria-targeting photosensitizer FEPT can produce reactive oxygen species (ROS) and hyperpyrexia upon 808 nm laser irradiation, resulting in mitochondrial dysfunction and photo-induced apoptosis via caspase-3 pathway. Phototherapy-induced hyperthermia or ROS triggers the release of immunogenic intracellular substrates from dying tumor cells, thereby promoting the activation of antitumor immunity. Herein, this work provides a practicable strategy to develop a molecular phototheranostic platform for imaging-guided cancer therapy via mitochondria-targeting.

Metabolic Labeling Strategy Boosted Antibacterial Efficiency for Photothermal and Photodynamic Synergistic Bacteria-Infected Wound Therapy.

Pathogenic bacteria infections bring about a substantial risk to human health. Given the development of antibiotic-resistance bacteria, alternative antibacterial strategies with great inactivation efficiency and bacteria-binding ability are extremely attractive. In this work, a metabolic labeling photosensitizer, prepared by the coupling of commercial IR820 and d-propargylglycine (a type of d-amino acid, DAA) via a straightforward one-step incubation (IR820-DAA), could metabolically be incorporated into the bacterial wall via enzymatic reactions, thus enhancing antibacterial efficiency. The laser energy at 808 nm could make IR820-DAA a synergistic photothermal/photodynamic agent for efficient antibacterial therapy and wound healing. Furthermore, IR820-DAA exhibits good water solubility and biological safety for clinical translation and even possesses biofilm degradation activity toward methicillin-resistant Staphylococcus aureus (MRSA). Overall, the proposed IR820-DAA holds great promise as a nonantibiotic tool for the treatment of bacteria-related diseases and offers a blueprint for building the precise synergistic antibacterial therapeutic platform.

Novel Organic-Inorganic Hybrid Polystyrene Nanoparticles with Trichromatic Luminescence for the Detection of Latent Fingerprints.

This article explored the application of novel organic-inorganic hybrid polystyrene nanoparticles (PSNPs) with trichromatic luminescence for the detection of latent fingerprints. The PSNPs were synthesized by encapsulated Eu(DBM)3phen, coumarin 6, and FDBT into the polystyrene nanoparticles through the swelling method and applied them to visualize latent fingerprints. The PSNPs had a spherical morphology with an average diameter of 310.7 nm, and they emitted trichromatic fluorescence (525 nm/570 nm/610 nm) under 365 nm excitation wavelength with green/yellow/red color under filters. They were less likely to aggregate, float or stain the background when treating fingerprints. The developed fingerprints with excellent clarity of ridges and contrast could be viewed, and the digital magnification of fluorescence-developed fingerprints provided more minutiae details about some regional patterns. The colorimetric and fluorescent trichromatic light could provide complementary signals without the background interference from fluorescent substrates and/or complex multicolor surfaces, which improved the applicability of fluorescent nanoparticles for fingerprints development. PSNPs are promising for the detection of latent fingerprints and practical criminal investigations with their ease of operation, eco-friendly properties, and excellent trichromatic optical performance.

PdIr Aerogels with Boosted Peroxidase-like Activity for a Sensitive Total Antioxidant Capacity Colorimetric Bioassay.

Metallic aerogels (MAs), imparting the active catalytic properties of nanostructured noble metals to macroscopic aerogels, draw tremendous interest in diverse fields owing to the unique features of three-dimensional interconnected channels, self-supported architectures, and pure metallic backbones. Moreover, flexible manipulation of compositions, high electrical conductivity, and abundant active sites of MAs contribute to the great potential to mimic natural enzymes. However, the cumbersome synthetic process takes a couple of hours to days, and unavoidable impurities usually impede surface electrons/mass transfer, posing the decrease of stability and enzyme-like activity of MAs. Here, a PdIr bimetallic aerogel prepared in the ethanol phase via spontaneous assembly and a surfactant-free strategy is reported. Gelation kinetics of PdIr aerogels in ethanol is increased with 2-4 orders of magnitude compared to the traditional preparation method in water. Owing to the intrinsic physicochemical properties, PdIr aerogels exhibit the high activity of peroxidase mimics using 3,3',5,5'-tetramethylbenzidine as a chromogenic probe. In addition, the PdIr aerogels maintain relatively high activity at an elevated temperature and pH of 3-7, demonstrating their good stability and survivability. Utilizing the exceptional peroxidase-like activity of PdIr aerogels, we realized the quantitative bioassay for H2O2 and total antioxidant capacity, indicating enormous potential in the quality evaluation of real samples.

Near-Infrared-II Bioimaging for in Vivo Quantitative Analysis.

Near-Infrared-II (NIR-II) bioimaging is a newly emerging visualization modality in real-time investigations of biological processes research. Owning to advances in reducing photon scattering and low tissue autofluorescence levels in NIR-II region (1,000-1700 nm), NIR-II bioimaging affords high resolution with increasing tissue penetration depth, and it shows greater application potential for in vivo detection to obtain more detailed qualitative and quantitative parameters. Herein, this review summarizes recent progresses made on NIR-II bioimaging for quantitative analysis. These emergences of various NIR-II fluorescence, photoacoustic (PA), luminescence lifetime imaging probes and their quantitative analysis applications are comprehensively discussed, and perspectives on potential challenges facing in this direction are also raised.

Polyaniline Nanovesicles for Photoacoustic Imaging-Guided Photothermal-Chemo Synergistic Therapy in the Second Near-Infrared Window.

Photoacoustic imaging-guided photothermal therapy in the second near-infrared (NIR-II) window shows promise for clinical deep-penetrating tumor phototheranostics. However, ideal photothermal agents in the NIR-II window are still rare. Here, the emeraldine salt of polyaniline (PANI-ES), especially synthesized by a one-pot enzymatic reaction on sodium bis(2-ethylhexyl) sulfosuccinate (AOT) vesicle surface (PANI-ES@AOT, λmax  ≈ 1000 nm), exhibits excellent dispersion in physiological environment and remarkable photothermal ability at pH 6.5 (photothermal conversion efficiency of 43.9%). As a consequence of the enhanced permeability and retention effect of tumors and the doping-induced photothermal effect of PANI-ES@AOT, this pH-sensitive NIR-II photothermal agent allows tumor acidity phototheranostics with minimized pseudosignal readout and subdued normal tissue damage. Moreover, the enhanced fluidity of vesicle membrane triggered by heating is beneficial for drug release and allows precise synergistic therapy for an improved therapeutic effect. This study highlights the potential of template-oriented (or interface-confined) enzymatic polymerization reactions for the construction of conjugated polymers with desired biomedical applications.

Metabolic Labeling of Peptidoglycan with NIR-II Dye Enables In Vivo Imaging of Gut Microbiota.

Deepening our understanding of mammalian gut microbiota has been greatly hampered by the lack of a facile, real-time, and in vivo bacterial imaging method. To address this unmet need in microbial visualization, we herein report the development of a second near-infrared (NIR-II)-based method for in vivo imaging of gut bacteria. Using d-propargylglycine in gavage and then click reaction with an azide-containing NIR-II dye, gut microbiota of a donor mouse was strongly labeled with NIR-II fluorescence on their peptidoglycan. The bacteria could be readily visualized in recipient mouse gut with high spatial resolution and deep tissue penetration under NIR irradiation. The NIR-II-based metabolic labeling strategy reported herein, provides, to the best of our knowledge, the first protocol for facile in vivo visualization of gut microbiota within deep tissues, and offers an instrumental tool for deciphering the complex biology of these gut "dark matters".

Rational design of a super-contrast NIR-II fluorophore affords high-performance NIR-II molecular imaging guided microsurgery.

In vivo molecular imaging in the "transparent" near-infrared II (NIR-II) window has demonstrated impressive benefits in reaching millimeter penetration depths with high specificity and imaging quality. Previous NIR-II molecular imaging generally relied on high hepatic uptake fluorophores with an unclear mechanism and antibody-derived conjugates, suffering from inevitable nonspecific retention in the main organs/skin with a relatively low signal-to-background ratio. It is still challenging to synthesize a NIR-II fluorophore with both high quantum yield and minimal liver-retention feature. Herein, we identified the structural design and excretion mechanism of novel NIR-II fluorophores for NIR-II molecular imaging with an extremely clean background. With the optimized renally excreted fluorophore-peptide conjugates, superior NIR-II targeting imaging was accompanied by the improved signal-to-background ratio during tumor detection with reducing off-target tissue exposure. An unprecedented NIR-II imaging-guided microsurgery was achieved using such an imaging platform, which provides us with a great preclinical example to accelerate the potential clinical translation of NIR-II imaging.

Repurposing Cyanine NIR-I Dyes Accelerates Clinical Translation of Near-Infrared-II (NIR-II) Bioimaging.

The significantly reduced tissue autofluorescence and scattering in the NIR-II region (1000-1700 nm) opens many exciting avenues for detailed investigation of biological processes in vivo. However, the existing NIR-II fluorescent agents, including many molecular dyes and inorganic nanomaterials, are primarily focused on complicated synthesis routes and unknown immunogenic responses with limited potential for clinical translation. Herein, the >1000 nm tail emission of conventional biocompatible NIR cyanine dyes with emission peaks at 700-900 nm is systematically investigated, and a type of bright dye for NIR-II imaging with high potential for accelerating clinical translation is identified. The asymmetry of the π domain in the S1 state of NIR cyanine dyes is proven to result in a twisted intramolecular charge-transfer process and NIR-II emission, establishing a general rule to guide future NIR-I/II fluorophore synthesis. The screened NIR dyes are identified to possess a bright emission tail in the NIR-II region along with high quantum yield, high molar-extinction coefficient, rapid fecal excretion, and functional groups amenable for bioconjugation. As a result, NIR cyanine dyes can be used for NIR-II imaging to afford superior contrast and real-time imaging of several biological models, facilitating the translation of NIR-II bioimaging to clinical theranostic applications.