Bright Aggregation‐Induced‐Emission Dots for Targeted Synergetic NIR‐II Fluorescence and NIR‐I Photoacoustic Imaging of Orthotopic Brain Tumors

Precise diagnostics are of significant importance to the optimal treatment outcomes of patients bearing brain tumors. NIR‐II fluorescence imaging holds great promise for brain‐tumor diagnostics with deep penetration and high sensitivity. This requires the development of organic NIR‐II fluorescent agents with high quantum yield (QY), which is difficult to achieve. Herein, the design and synthesis of a new NIR‐II fluorescent molecule with aggregation‐induced‐emission (AIE) characteristics is reported for orthotopic brain‐tumor imaging. Encapsulation of the molecule in a polymer matrix yields AIE dots showing a very high QY of 6.2% with a large absorptivity of 10.2 L g^?1 cm^?1 at 740 nm and an emission maximum near 1000 nm. Further decoration of the AIE dots with c‐RGD yields targeted AIE dots, which afford specific and selective tumor uptake, with a high signal/background ratio of 4.4 and resolution up to 38 µm. The large NIR absorptivity of the AIE dots facilitates NIR‐I photoacoustic imaging with intrinsically deeper penetration than NIR‐II fluorescence imaging and, more importantly, precise tumor‐depth detection through intact scalp and skull. This research demonstrates the promise of NIR‐II AIE molecules and their dots in dual NIR‐II fluorescence and NIR‐I photoacoustic imaging for precise brain cancer diagnostics.     

Molecular Engineering of an Organic NIR‐II Fluorophore with Aggregation‐Induced Emission Characteristics for In Vivo Imaging

Design and synthesis of new fluorophores with emission in the second near‐infrared window (NIR‐II, 1000–1700 nm) have fueled the advancement of in vivo fluorescence imaging. Organic NIR‐II probes particularly attract tremendous attention due to excellent stability and biocompatibility, which facilitate clinical translation. However, reported organic NIR‐II fluorescent agents often suffer from low quantum yield and complicated design. In this study, the acceptor unit of a known NIR‐I aggregation‐induced emission (AIE) luminogen (AIEgen) is molecularly engineered by varying a single atom from sulfur to selenium, leading to redshifted absorption and emission spectra. After formulation of the newly prepared AIEgen, the resultant AIE nanoparticles (referred as L897 NPs) have an emission tail extending to 1200 nm with a high quantum yield of 5.8%. Based on the L897 NPs, noninvasive vessel imaging and lymphatic imaging are achieved with high signal‐to‐background ratio and deep penetration. Furthermore, the L897 NPs can be used as good contrast agents for tumor imaging and image‐guided surgery due to the high tumor/normal tissue ratio, which peaks at 9.0 ± 0.6. This work suggests a simple strategy for designing and manufacturing NIR‐II AIEgens and demonstrates the potential of NIR‐II AIEgens in vessel, lymphatic, and tumor imaging.     

Hierarchically Nanostructured Hybrid Platform for Tumor Delineation and Image‐Guided Surgery via NIR‐II Fluorescence and PET Bimodal Imaging

Bimodal imaging with fluorescence in the second near infrared window (NIR‐II) and positron emission tomography (PET) has important significance for tumor diagnosis and management because of complementary advantages. It remains challenging to develop NIR‐II/PET bimodal probes with high fluorescent brightness. Herein, bioinspired nanomaterials (melanin dot, mesoporous silica nanoparticle, and supported lipid bilayer), NIR‐II dye CH‐4T, and PET radionuclide ⁶⁴Cu are integrated into a hybrid NIR‐II/PET bimodal nanoprobe. The resultant nanoprobe exhibits attractive properties such as highly uniform tunable size, effective payload encapsulation, high stability, dispersibility, and biocompatibility. Interestingly, the incorporation of CH‐4T into the nanoparticle leads to 4.27‐fold fluorescence enhancement, resulting in brighter NIR‐II imaging for phantoms in vitro and in situ. Benefiting from the fluorescence enhancement, NIR‐II imaging with the nanoprobe is carried out to precisely delineate and resect tumors. Additionally, the nanoprobe is successfully applied in tumor PET imaging, showing the accumulation of the nanoprobe in a tumor with a clear contrast from 2 to 24 h postinjection. Overall, this hierarchically nanostructured platform is able to dramatically enhance fluorescent brightness of NIR‐II dye, detect tumors with NIR‐II/PET imaging, and guide intraoperative resection. The NIR‐II/PET bimodal nanoprobe has high potential for sensitive preoperative tumor diagnosis and precise intraoperative image‐guided surgery.     

A Targeted and FRET‐Based Ratiometric Fluorescent Nanoprobe for Imaging Mitochondrial Hydrogen Peroxide in Living Cells

Hydrogen peroxide (H₂O₂) is a prominent member of the reactive oxygen species family and plays crucial roles in living organisms, thus detecting H₂O₂ and elucidating its biological functions has become an important area of biological and biomedical research. Herein, a multifunctional fluorescent nanoprobe is demonstrated for detecting mitochondrial H₂O₂. The nanoprobe is prepared by covalently linking a mitochondria‐targeting ligand (triphenylphosphonium, TPP) and a H₂O₂ recognition element (PFl) onto carbon dots (CDs). For this nanoprobe, the CD serves as the carrier and the FRET donor. In the presence of H₂O₂, the PFl moieties on a CD undergo structural and spectral conversion, affording the nanoplatform a FRET‐based ratiometric probe for H₂O₂. The nanoprobe displays excellent water dispersibility, high sensitivity and selectivity, satisfactory cell permeability, and very low cytotoxicity. Following the living cell uptake, this nanoprobe can specifically target and stain the mitochondria; and it can detect the exogenous H₂O₂ in L929 cells, as well as the endogenously produced mitochondrial H₂O₂ in Raw 264.7 cells upon stimulation by PMA. This study shows that CDs can serve as promising nano‐carriers for fabricating practical multifunctional fluorescent nanosensors.     

A Single Composition Architecture‐Based Nanoprobe for Ratiometric Photoacoustic Imaging of Glutathione (GSH) in Living Mice

As one of the reduction species, glutathione (GSH) plays a tremendous role in regulating the homeostasis of redox state in living body. Accurate imaging of GSH in vivo is highly desired to provide a real‐time visualization of physiological and pathological conditions while it is still a big challenge. Recently developed photoacoustic imaging (PAI) with high resolution and deep penetration characteristics is more promising for in vivo GSH detection. However, its application is dramatically limited by the difficult designation of photoacoustic probes with changeable near‐infrared (NIR)‐absorption under reductive activation. A cyanine derivative‐based activatable probe is developed for in vivo ratiometric PAI of GSH for the first time. The probe is structurally designed to output ratiometric signals toward GSH in NIR‐absorption region based on the cleavage of disulfide bond followed by a subsequent exchange between the secondary amine and sulfydryl group formed. Such a ratiometric manner provides high signal‐to‐noise imaging of blood vessels and their surrounding areas in tumor. Concomitantly, it also exhibits good specificity toward GSH over other thiols. Furthermore, the single composition architecture of the probe effectively overcomes the leakage issue compared with traditional multicomposition architecture‐based nanoprobe, thus enhancing the imaging accuracy and fidelity in living body.     

Modular Integration of Upconverting Nanocrystal–Dendrimer Composites for Folate Receptor‐Specific NIR Imaging and Light‐Triggered Drug Release

Upconversion nanocrystals (UCNs) display near‐infrared (NIR)‐responsive photoluminescent properties for NIR imaging and drug delivery. The development of effective strategies for UCN integration with other complementary nanostructures for targeting and drug conjugation is highly desirable. This study reports on a core/shell‐based theranostic system designed by UCN integration with a folate (FA)‐conjugated dendrimer for tumor targeting and with photocaged doxorubicin as a cytotoxic agent. Two types of UCNs (NaYF₄:Yb/Er (or Yb/Tm); diameter = ≈50 to 54 nm) are described, each displaying distinct emission properties upon NIR (980 nm) excitation. The UCNs are surface modified through covalent attachment of photocaged doxorubicin (ONB‐Dox) and a multivalent FA‐conjugated polyamidoamine (PAMAM) dendrimer G5(FA)₆ to prepare UCN@(ONB‐Dox)(G5FA). Surface plasmon resonance experiments performed with G5(FA)₆ dendrimer alone show nanomolar binding avidity (K_D = 5.9 × 10⁻⁹m ) to the folate binding protein. This dendrimer binding corresponds with selective binding and uptake of UCN@(ONB‐Dox)(G5FA) by FAR‐positive KB carcinoma cells in vitro. Furthermore, UCN@(ONB‐Dox)(G5FA) treatment of FAR(+) KB cells inhibits cell growth in a light dependent manner. These results validate the utility of modularly integrated UCN‐dendrimer nanocomposites for cell type specific NIR imaging and light‐controlled drug release, thus serving as a new theranostic system.     

Miniature Hollow Gold Nanorods with Enhanced Effect for In Vivo Photoacoustic Imaging in the NIR‐II Window

The miniaturization of gold nanorods exhibits a bright prospect for intravital photoacoustic imaging (PAI) and the hollow structure possesses a better plasmonic property. Herein, miniature hollow gold nanorods (M‐AuHNRs) (≈46 nm in length) possessing strong plasmonic absorbance in the second near‐infrared (NIR‐II) window (1000–1350 nm) are developed, which are considered as the most suitable range for the intravital PAI. The as‐prepared M‐AuHNRs exhibit 3.5 times stronger photoacoustic signal intensity than the large hollow Au nanorods (≈105 nm in length) at 0.2 optical density under 1064 nm laser irradiation. The in vivo biodistribution measurement shows that the accumulation in tumor of miniature nanorods is twofold as high as that of the large counterpart. After modifying with a tumor‐targeting molecule and fluorochrome, in living tumor‐bearing mice, the M‐AuHNRs group gives a high fluorescence intensity in tumors, which is 3.6‐fold that of the large ones with the same functionalization. Moreover, in the intravital PAI of living tumor‐bearing mice, the M‐AuHNRs generate longer‐lasting and stronger photoacoustic signal than the large counterpart in the NIR‐II window. Overall, this study presents the fabrication of M‐AuHNRs as a promising contrast agent for intravital PAI.     

Through Scalp and Skull NIR‐II Photothermal Therapy of Deep Orthotopic Brain Tumors with Precise Photoacoustic Imaging Guidance

Brain tumor is one of the most lethal cancers owing to the existence of blood–brain barrier and blood–brain tumor barrier as well as the lack of highly effective brain tumor treatment paradigms. Herein, cyclo(Arg‐Gly‐Asp‐D‐Phe‐Lys(mpa)) decorated biocompatible and photostable conjugated polymer nanoparticles with strong absorption in the second near‐infrared (NIR‐II) window are developed for precise photoacoustic imaging and spatiotemporal photothermal therapy of brain tumor through scalp and skull. Evidenced by the higher efficiency to penetrate scalp and skull for 1064 nm laser as compared to common 808 nm laser, NIR‐II brain‐tumor photothermal therapy is highly effective. In addition, via a real‐time photoacoustic imaging system, the nanoparticles assist clear pinpointing of glioma at a depth of almost 3 mm through scalp and skull with an ultrahigh signal‐to‐background ratio of 90. After spatiotemporal photothermal treatment, the tumor progression is effectively inhibited and the survival spans of mice are significantly extended. This study demonstrates that NIR‐II conjugated polymer nanoparticles are promising for precise imaging and treatment of brain tumors.     

Precursor‐Transformation Strategy Preparation of CuPx Nanodots–Decorated CoP3 Nanowires Hybrid Catalysts for Boosting pH‐Universal Electrocatalytic Hydrogen Evolution

The development of earth‐abundant, low cost, and versatile electrocatalysts for producing hydrogen from water electrolysis is still challenging. Herein, based on high hydrogen evolution reaction (HER) activity of transition metal phosphides, a CoP₃ nanowire decorated with copper phosphides (denoted as CuP_x) nanodots structures synthesized through a simple and easily scalable precursor‐transformation strategy is reported as a highly efficient HER catalyst. By decorating with CuP_x nanodots, the optimized CoP₃ nanowires electrode exhibits excellent catalytic activity and long‐term durability for HER in alkaline conditions, achieving a low overpotential of 49.5 mV at a geometrical catalytic current density of 10 mA cm^?2 with a small Tafel slope of 58.0 mV dec^?1, while also performing quite well in neutral and acidic media. Moreover, its overall performance exceeds most of the reported state‐of‐the‐art catalysts, especially under high current density of 100 mA cm^?2, demonstrating its potential as a promising versatile pH universal electrocatalyst for efficient water electrolysis. These results indicate that the incorporation of earth‐abundant stable element copper can significantly enhance catalytic activity, which widens the application range of copper and provides a new path for design and selection of HER catalysts.     

In Situ Synthesis of MoP Nanoflakes Intercalated N‐Doped Graphene Nanobelts from MoO3–Amine Hybrid for High‐Efficient Hydrogen Evolution Reaction

Molybdenum phosphide (MoP) is a promising non‐noble‐metal electrocatalyst in the hydrogen evolution reaction (HER), but practical implementation is impeded by the sluggish HER kinetics and poor chemical stability. Herein, a novel high‐efficiency HER electrocatalyst comprising MoP nanoflakes intercalated nitrogen‐doped graphene nanobelts (MoP/NG), which are synthesized by one‐step thermal phosphiding organic–inorganic hybrid dodecylamine (DDA) inserted MoO₃ nanobelts, is reported. The intercalated DDA molecules are in situ carbonized into the NG layer and the sandwiched MoO₃ layer is converted into MoP nanoflakes which are intercalated between the NG layers forming the alternatingly stacked MoP/NG hybrid nanobelts. The MoP nanoflakes provide abundant edge sites and the sandwiched MoP/NG hybrid enables rapid ion/electron transport thus yielding excellent electrochemical activity and stability for HER. The MoP/NG shows a low overpotential of 94 mV at 10 mA cm⁻², small Tafel slope of 50.1 mV dec⁻¹, and excellent electrochemical stability with 99.5% retention for over 22 h.