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Optical imaging in the second near-infrared (NIR-II; 900–1880 nm) window is currently a popular research topic in the field of biomedical imaging. This study aimed to explore the application value of NIR-II fluorescence imaging in foot and ankle surgeries. A lab-established NIR-II fluorescence surgical navigation system was developed and used to navigate foot and ankle surgeries which enabled obtaining more high-spatial-frequency information and a higher signal-to-background ratio (SBR) in NIR-II fluorescence images compared to NIR-I fluorescence images; our result demonstrates that NIR-II imaging could provide higher-contrast and larger-depth images to surgeons. Three types of clinical application scenarios (diabetic foot, calcaneal fracture, and lower extremity trauma) were included in this study. Using the NIR-II fluorescence imaging technique, we observed the ischemic region in the diabetic foot before morphological alterations, accurately determined the boundary of the ischemic region in the surgical incision, and fully assessed the blood supply condition of the flap. NIR-II fluorescence imaging can help surgeons precisely judge surgical margins, detect ischemic lesions early, and dynamically trace the perfusion process. We believe that portable and reliable NIR-II fluorescence imaging equipment and additional functional fluorescent probes can play crucial roles in precision surgery.

Rheumatoid arthritis (RA) is a systemic autoimmune disorder characterized by excessive proliferation of rheumatoid arthritis synovial fibroblasts (RASFs) and accumulation of inflammatory cytokines. Exploring the suppression of RASFs and modulation of the RA microenvironment is considered a comprehensive strategy for RA. In this work, specifically activated nanoagents (MAHI NGs) based on the hypoxic and weakly acidic RA microenvironment are developed to achieve a second near‐infrared fluorescence (NIR‐II FL)/photoacoustic (PA) dual‐model imaging‐guided multi‐treatment. Due to optimal size, the MAHI NGs passively accumulate in the diseased joint region and undergo rapid responsive degradation, precisely releasing functionalized components: endogenous melanin‐nanoparticles (MNPs), hydrogen gas (H2), and indocyanine green (ICG). The released MNPs play a crucial role in ablating RASFs within the RA microenvironment through photothermal therapy (PTT) guided by accurate PA imaging. However, the regional hyperthermia generated by PTT may exacerbate reactive oxygen species (ROS) production and inflammatory response following cell lysis. Remarkably, under the acidic microenvironment, the controlled release of H2 exhibits precise synergistic antioxidant and anti‐inflammatory effects with MNPs. Moreover, the ICG, the second near‐infrared dye currently approved for clinical use, possesses excellent NIR‐II FL imaging properties that facilitate the diagnosis of deep tissue diseases and provide the right time‐point for PTT. [ABSTRACT FROM AUTHOR]

The precise theranostics of rheumatoid arthritis (RA) remains a formidable challenge in clinical practice. Exploring novel applications of contemporary therapeutic approaches like chemo‐radiotherapy is promising as a highly effective strategy for RA. Herein, a novel activatable nanoradiosensitizer‐40 (denoted as IRnR‐40) is developed, based on encapsulating the clinically approved drugs cisplatin (DDP) and indocyanine green (ICG) within a gelatin shell to achieve second near‐infrared fluorescence (NIR‐II FL) imaging‐guided safe‐dose synergetic chemo‐radiotherapy. The high concentration of matrix metalloproteinase‐9 (MMP‐9) in the RA microenvironment plays a pivotal role in triggering the responsive degradation of IRnR‐40, leading to the rapid release of functional molecules DDP and ICG. The released ICG serves the dual purpose of illuminating the inflamed joints to facilitate accurate target volume delineation for guiding radiotherapy, as well as acting as a real‐time reporter for quantifying the release of DDP to monitor efficacy. Meanwhile, the released DDP achieves highly effective synergistic chemotherapy and radiosensitization for RA via the dual reactive oxygen species (ROS)‐mediated mitochondrial apoptotic pathway. To sum up, this activatable nanoradiosensitizer IRnR‐40 is believed to be the first attempt to achieve efficient NIR‐II FL imaging‐guided safe‐dose chemo‐radiotherapy for RA, which provides a new paradigm for precise theranostics of refractory benign diseases. [ABSTRACT FROM AUTHOR]

Fluorescence imaging in the second near‐infrared (NIR‐II) window holds great promise for in vivo visualization of amyloid‐β (Aβ) pathology, which can facilitate characterization and deep understanding of Alzheimer's disease (AD); however, it has been rarely exploited. Herein, we report the development of NIR‐II fluorescent reporters with a donor‐π‐acceptor (D‐π‐A) architecture for specific detection of Aβ plaques in AD‐model mice. Among all the designed probes, DMP2 exhibits the highest affinity to Aβ fibrils and can specifically activate its NIR‐II fluorescence after binding to Aβ fibrils via suppressed twisted intramolecular charge transfer (TICT) effect. With suitable lipophilicity for ideal blood–brain barrier (BBB) penetrability and deep‐tissue penetration of NIR‐II fluorescence, DMP2 possesses specific detection of Aβ plaques in in vivo AD‐model mice. Thus, this study presents a potential agent for non‐invasive imaging of Aβ plaques and deep deciphering of AD progression. [ABSTRACT FROM AUTHOR]

Phototheranositcs has recently aroused extreme attention due to its exceptional advantages. However, the poor photothernostic efficiency, limited penetration depth, strong oxygen-dependence, and inevitable damage to normal tissue of conventional photothernostic materials severely hindered their total theranostic efficacy. Herein, a series of near-infrared second (NIR-II) photosensitizers (PSs) featuring aggregation-induced emission (AIE), NIR-II fluorescence imaging (FLI), type I photodynamic therapy (PDT) and mild-temperature photothermal therapy (PTT) are constructed through dual-strategy methods combining donor group engineering and fluorination engineering. Profiting from sufficient molecular rotors and high electronegativity of fluorine, the developed 2-(2-((5-(4-((4-(diphenylamino)phenyl)(phenyl)amino)phenyl)thiophen-2-yl)methylene)-5,6-difluoro-3-oxo-2,3-dihydro-1H-inden-1-ylidene)malononitrile (BTS-2F) and 2-(2-((5-(4-(bis(4-(diphenylamino)phenyl)amino)phenyl)thiophen-2-yl)methylene)-5,6-difluoro-3-oxo-2,3-dihydro-1H-inden-1-ylidene)malononitrile (TTS-2F) are endowed with NIR-II AIE property, high radical reactive oxygen species (ROS) generation ability and mild-temperature photothermal conversion. Through thin film hydration method, the prepared BTS-2F and TTS-2F loaded liposomes exhibit significant NIR-II FLI and improved type-I PDT/mild-temperature PTT therapy under laser irradiation both in vitro and orthotopic 4T1 mice models., (© 2024 Wiley‐VCH GmbH.)

Fluorescence imaging is a noninvasive technique that affords real‐time fast feedback, high sensitivity, and harmless radiation and is thus effective in visualizing the anatomy and function of organs. Recently, second near‐infrared (NIR‐II, 1000–1700 nm) fluorescence imaging emerged as a popular imaging technique for both fundamental research and clinical practice, with strong potential for applications in the field of biomedicine. It affords a high signal‐to‐noise ratio and high spatial and temporal resolutions for the imaging of deep tissue owing to reduced scattering, minimal absorption, and negligible autofluorescence. Herein, the performance and advancement of fluorophores for NIR‐II fluorescence imaging are summarized. Further, the challenges to the NIR‐II fluorophores in terms of emission wavelengths, quantum yields, stability, targeting, and biocompatibility are discussed. Finally, perspective on the current development and the orientation for future studies on NIR‐II imaging, such as dual‐mode imaging, multiplexed imaging, surgical navigation, integrated diagnosis and treatment, and biosensing are discussed.

To detect the therapeutic efficacy of CelTrac1000-labeled hair follicle epidermal neural crest stem cells (EPI-NCSCs) on repairing facial nerve defects by second near-infrared (NIR-II) fluorescence imaging. Firstly, CelTrac1000-labeled EPI-NCSCs were microinjected into the acellular nerve allografts (ANAs) to bridge a 10-mm-long gap in the buccal branch of facial nerve in adult rats. Then, Celtrac1000-labeled EPI-NCSCs were detected by NIR-II fluorescence imaging system to visualize the behavior of the transplanted cells in vivo. Additionally, the effect of the transplanted EPI-NCSCs on repairing facial nerve defect was examined. Through 14 weeks of dynamic observation, the transplanted EPI-NCSCs survived in the ANAs in vivo after surgery. Meanwhile, the region of the NIR-II fluorescence signals was gradually limited to be consistent with the direction of the regenerative nerve segment. Furthermore, the results of functional and morphological analysis showed that the transplanted EPI-NCSCs could promote the recovery of facial paralysis and neural regeneration after injury. Our research provides a novel way to track the transplanted cells in preclinical studies of cell therapy for facial paralysis, and demonstrates the therapeutic potential of EPI-NCSCs combined with ANAs in bridging rat facial nerve defects. [ABSTRACT FROM AUTHOR]

In this work, we have successfully constructed multifunctional GSH-responsive H 2 S nanogenerators (BDMA NGs), achieving activable precise second near-infrared fluorescence (NIR-II FL)/photoacoustic (PA) bimodal imaging-guided gas/chemotherapy synergistic therapy in rheumatoid arthritis. [Display omitted] • In-situ GSH-responsive gas nanogenerators for active NIR-II FL/PA imaging. • Multifunctional nanogenerators for integrating localization and therapy monitoring. • Clarifying the anti-RA intricate mechanism by macrophage reprogramming. Rheumatoid arthritis (RA) is currently one of the most common systemic autoimmune disorders, with no clinically effective theranostics. Therapeutic manipulation of the gasotransmitter hydrogen sulfide (H 2 S) has exhibited promising potential as an innovative strategy in RA, whereas limited with non-targeting, low solubility, and systemic toxicity. In this work, based on the physicochemical and structural advantages of stimulus-responsive nanotechnology, we develop multifunctional glutathione (GSH)-responsive H 2 S nanogenerators (BDMA NGs), achieving activatable precise second near-infrared fluorescence (NIR-II FL)/photoacoustic (PA) bimodal imaging-guided gas/chemotherapy synergistic therapy. Contributed to the suitable size and excellent biocompatibility, the BDMA NGs accumulate passively in the RA region and then feature a responsive deformation reaction with GSH to release functional small molecules: H 2 S and methotrexate (MTX). The H 2 S undergoes a mineralization process with Ag+ ions in situ, resulting in the rapid formation of Ag 2 S to "turn on" the NIR-II FL/PA signals. Remarkably, the effective generation of H 2 S downregulates hypoxia-inducible factor-1 α (HIF-1 α) and promotes nuclear factor erythroid 2-related factor 2 (Nrf2) nuclear translocation, thereby restoring homeostasis in the RA microenvironment and facilitating the reprogramming of pro-inflammatory macrophages (M1) into anti-inflammatory phenotype (M2). Moreover, the controlled release of MTX, clinically approved drug for RA, synergistically promotes repolarization to further suppress local inflammation. Overall, the H 2 S-based nanogenerators BDMA NGs present a sophisticated and versatile strategy for implementing stimuli-responsive imaging and M1-to-M2 repolarization, demonstrating significant potential in the theranostics of RA and clinical transformation. [ABSTRACT FROM AUTHOR]

Molecular fluorophores emitting in the second near-infrared (NIR-II, 1000-1700 nm) window with strong optical harvesting and high quantum yields hold great potential for in vivo deep-tissue bioimaging and high-resolution biosensing. Recently, J-aggregates are harnessed to engineer long-wavelength NIR-II emitters and show unique superiority in tumor detection, vessel mapping, surgical navigation, and phototheranostics due to their bathochromic-shifted optical bands in the required slip-stacked arrangement aggregation state. However, despite the preliminary progress of NIR-II J-aggregates and theoretical study of structure-property relationships, further paradigms of NIR-II J-aggregates remain scarce due to the lack of study on aggregated fluorophores with slip-stacked fashion. In this effort, how to utilize the specific molecular structure to form slip-stacked packing motifs with J-type aggregated exciton coupling is emphatically elucidated. First, several molecular regulating strategies to achieve NIR-II J-aggregates containing intermolecular interactions and external conditions are positively summarized and deeply analyzed. Then, the recent reports on J-aggregates for NIR-II bioimaging and theranostics are systematically summarized to provide a clear reference and direction for promoting the development of NIR-II organic fluorophores. Eventually, the prospective efforts on ameliorating and promoting NIR-II J-aggregates to further clinical practices are outlined., (© 2023 Wiley-VCH GmbH.)

• The prepared SP94-PEG-p(AAm- co -AN) were biocompatible and depolymerized at the UCST of 43 °C. • SPLI could trigger a rapid release of encapsulated drug and induce ICD in tumors under NIR-II light irradiation. • SPLI combined with a PD-1 simultaneously achieved multiple therapies for HCC with the guidance of NIR-II fluorescence imaging. Lenvatinib (LEN) combined with immune checkpoint PD-1 blockade is among the most effective treatment strategies for advanced hepatocellular carcinoma (HCC) and has been deemed a breakthrough therapy by the Food and Drug Administration. However, this combined strategy is associated with disadvantages such as non-tumor targeted aggregation and low oral bioavailability after long-term administration of LEN, and some patients show poor responses to immunotherapy as well. To overcome these drawbacks, SP94 peptide-modified thermal-sensitive micelles (SP94-poly(ethylene glycol)-poly(acrylamide- co -acrylonitrile, SP94-PEG-p(AAm- co -AN)) with an upper critical solution temperature (UCST) of 43 °C were designed. The micelles were further co-loaded with LEN and IR-1061-Acridine (IR-1061-AcD) to simultaneously achieve small molecule targeted drug, photothermal and photodynamic therapy for HCC under the guidance of near-infrared second-region (NIR-II) fluorescence imaging. After intravenous injection, the co-loaded micelles (SP94-PEG-p(AAm- co -AN)/LEN/IR-1061-AcD, SPLI) showed greater accumulation at tumor sites because SP94 has a high affinity for glucoregulatory protein 78 (GRP78), which is overexpressed on HCC cells. Given these HCC-targeted effects, SPLI appeared useful for NIR-II fluorescence imaging, enabling real-time tumor monitoring and surgical resection. In addition, SPLI could extensively induce immunogenic cell death in tumors, resulting in beneficial systemic immune responses. When further combined with anti-PD-1 immunotherapy, SPLI displayed a superior potential in suppressing tumor growth and metastasis while avoiding immune inhibition. Taken together, our study suggests that the aforementioned combinational strategy could serve as a desired multifunctional approach for HCC management. [ABSTRACT FROM AUTHOR]

Colorectal cancer (CRC) ranks as the third common and the fourth lethal cancer type worldwide. Immune checkpoint blockade therapy demonstrates great efficacy in a subset of metastatic CRC patients, but precise activation of the antitumor immune response at the tumor site is still challenging. Here a versatile prodrug nanoparticle for second near-infrared (NIR-II) fluorescence imaging-guided combinatory immunotherapy of CRC is reported. The prodrug nanoparticles are constructed with a polymeric oxaliplatin prodrug (PBOXA) and a donor-spacer-acceptor-spacer-donor type small molecular fluorophore TQTCD. The later displays large Stokes shift (>300 nm), fluorescence emission over 1000 nm, and excellent photothermal conversion performance for NIR-II fluorescence imaging-guided photothermal therapy (PTT). The prodrug nanoparticles show seven times higher intratumoral OXA accumulation than free oxaliplatin. TQTCD-based PTT and PBOXA-induced chemotherapy trigger immunogenic cell death of the tumor cells and elicit antitumor immune response in a spatiotemporally controllable manner. Further combination of the prodrug nanoparticle-based PTT/chemotherapy with programmed death ligand 1 blockade significantly promotes intratumoral infiltration of the cytotoxic T lymphocytes and eradicates the CRC tumors. The NIR-II fluorescence imaging-guided immunotherapy may provide a promising approach for CRC treatment., (© 2021 Wiley-VCH GmbH.)

Organic theranostic nanomedicine has precision multimodel imaging capability and concurrent therapeutics under noninvasive imaging guidance. However, the rational design of desirable multifunctional organic theranostics for cancer remains challenging. Rational engineering of organic semiconducting nanomaterials has revealed great potential for cancer theranostics largely owing to their intrinsic diversified biophotonics, easy fabrication of multimodel imaging platform, and desirable biocompatibility. Herein, a novel all-organic nanotheranostic platform (TPATQ-PNP NPs) is developed by exploiting the self-assembly of a semiconducting small molecule (TPATQ) and a new synthetic high-density nitroxide radical-based amphiphilic polymer (PNP). The nitroxide radicals act as metal-free magnetic resonance imaging agent through shortened longitudinal relaxation times, and the semiconducting molecules enable ultralow background second near-infrared (NIR-II, 1000-1700 nm) fluorescence imaging. The as-prepared TPATQ-PNP NPs can light up whole blood vessels of mice and show precision tumor-locating ability with synergistic (MR/NIR-II) imaging modalities. The semiconducting molecules also undergo highly effective photothermal conversion in the NIR region for cancer photothermal therapy guided by complementary tumor diagnosis. The designed multifunctional organic semiconducting self-assembly provides new insights into the development of a new platform for cancer theranostics., (© 2021 Wiley-VCH GmbH. This article has been contributed to by US Government employees and their work is in the public domain in the USA.)

Aggregation-induced emission (AIE) fluorophores with second near-infrared window (NIR-II) fluorescence are very promising for in vivo imaging because they emit fluorescence in an aggregated state and provide desirable imaging resolution and depth. Up to now, only a limited number of NIR-II AIE fluorophores have been developed. Therefore, synthesizing novel NIR-II AIE fluorophores and investigating structural effects on their photophysical properties are very important for the development of AIE probes. In this work, we synthesized two donor-acceptor-donor-type NIR fluorophores with emissions extending into the NIR-II window named DPTQ-PhPTZ and DPTQ-PhPXZ with phenothiazine (PTZ) and phenoxazine (PXZ) derivatives as the electron donors, respectively, and studied their photophysical properties via theoretical and experimental approaches as well as the properties in NIR-II in vivo imaging. The PTZ and PXZ moieties provided typical AIE characteristics. Despite the very similar chemical structures of PTZ and PXZ, DPTQ-PhPTZ and DPTQ-PhPXZ exhibited rather different photophysical properties, for example, compared to DPTQ-PhPTZ, DPTQ-PhPXZ had higher quantum yield (QY) both in solution and in the aggregated state and its QY was less sensitive to solvent polarity. After being coated with an amphiphilic copolymer F-127, the fluorophores maintained fluorescence, and the formed fluorescent polymer nanoparticles (NPs) had satisfactory tumor accumulation and biocompatibility, implying that they are applicable for in vivo tumor detection.

Development of single near‐infrared (NIR) laser triggered phototheranostics for multimodal imaging guided combination therapy is highly desirable but is still a big challenge. Herein, a novel small‐molecule dye DPP‐BT is designed and synthesized, which shows strong absorption in the first NIR window (NIR‐I) and fluorescence emission in the second NIR region (NIR‐II). Such a dye not only acts as a dual‐modal contrast agent for NIR‐II fluorescence and photoacoustic (PA) imaging, but also serves as a combined therapeutic agent for photothermal therapy (PTT) and photodynamic therapy (PDT). The single NIR laser triggered all‐in‐one phototheranostic nanoparticles are constructed by encapsulating the dye DPP‐BT, chemotherapy drug DOX, and natural phase‐change materials with a folic acid functionalized amphiphile. Notably, under NIR laser irradiation, DOX can effectively release from such nanoparticles via NIR‐induced hyperthermia of DPP‐BT. By intravenous injection of such nanoparticles into Hela tumor‐bearing mice, the tumor size and location can be accurately observed via NIR‐II fluorescence/PA dual‐modal imaging. From in vitro and in vivo therapy results, such nanoparticles simultaneously present remarkable antitumor efficacy by PTT/PDT/chemo combination therapy, which is triggered by a single NIR laser. Overall, this work provides an innovative strategy to design and construct all‐in‐one nanoplatforms for clinical phototheranostics. [ABSTRACT FROM AUTHOR]

Our exploiting versatile multimodal theranostic agent aims to integrate the complementary superiorities of photoacoustic imaging (PAI), second near-infrared (NIR-II, 1000-1700) fluorescence and T 1 -weighted magnetic resonance imaging (MRI) with an ultimate objective of perfecting cancer diagnosis, thus improving cancer therapy efficacy. Herein, we engineered and prepared a water-soluble gadolinium-chelated conjugated polymer-based theranostic nanomedicine (PFTQ-PEG-Gd NPs) for in vivo tri-mode PA/MR/NIR-II imaging-guided tumor photothermal therapy (PTT). Methods : We firstly constructed a semiconducting polymer composed of low-bandgap donor-acceptor (D-A) which afforded the strong NIR absorption for PAI/PTT and long fluorescence emission to NIR-II region for in vivo imaging. Then, the remaining carboxyl groups of the polymeric NPs could effectively chelate with Gd 3+ ions for MRI. The in vitro characteristics of the PFTQ-PEG-Gd NPs were studied and the in vivo multimode imaging as well as anti-tumor efficacy of the NPs was evaluated using 4T1 tumor-bearing mice. Results : The obtained theranostic agent showed excellent chemical and optical stability as well as low biotoxicity. After 24 h of systemic administration using PQTF-PEG-Gd NPs, the tumor sites of living mice exhibited obvious enhancement in PA, NIR-II fluorescence and positive MR signal intensities. Better still, a conspicuous tumor growth restraint was detected under NIR light irradiation after administration of PQTF-PEG-Gd NPs, indicating the efficient photothermal potency of the nano-agent. Conclusion : we triumphantly designed and synthesized a novel and omnipotent semiconducting polymer nanoparticles-based theranostic platform for PAI, NIR-II fluorescence imaging as well as positive MRI-guided tumor PTT in living mice. We expect that such a novel organic nano-platform manifests a great promise for high spatial resolution and deep penetration cancer theranostics., Competing Interests: Competing Interests: The authors have declared that no competing interest exists.

Optical imaging has played a pivotal role in biology and medicine, but it faces challenges of relatively low tissue penetration and poor signal-to-background ratio due to light scattering and tissue autofluorescence. To overcome these issues, second near-infrared fluorescence, self-luminescence, and photoacoustic imaging have recently emerged, which utilize an optical region with reduced light-tissue interactions, eliminate real-time light excitation, and detect acoustic signals with negligible attenuation, respectively. Because there are only a few endogenous molecules absorbing or emitting above the visible region, development of contrast agents is essential for those deep-tissue optical imaging modalities. Organic semiconducting agents with π-conjugated frameworks can be synthesized to meet different optical imaging requirements due to their easy chemical modification and legible structure-property relation. Herein, the deep-tissue optical imaging applications of organic semiconducting agents including small-molecule agents and nanoparticle derivatives are summarized. In particular, the molecular engineering and nanoformulation approaches to further improve the tissue penetration and detection sensitivity of these optical imaging modalities are highlighted. Finally, current challenges and potential opportunities in this emerging subfield of biomedical imaging are discussed., (© 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)