"Afterglow" Photodynamic Therapy Based on Carbon Dots Embedded Silica Nanoparticles for Nondestructive Teeth Whitening.

Teeth staining is a common dental health challenge in many parts of the world. Traditional teeth whitening techniques often lead to enamel damage and soft tissue toxicity due to the use of bioincompatible whitening reagents and continuous strong light irradiation. Herein, an "afterglow" photodynamic therapy (aPDT) for teeth whitening is proposed, which is realized by energy transition pathways of intersystem crossing. The covalent and hydrogen bonds formed by carbon dots embedded in silica nanoparticles (CDs@SiO2) facilitate the passage of energy through intersystem crossing (ISC), thereby extending the half-life of reactive oxygen species (ROS). The degradation efficiency of aPDT on dyes was higher than 95% in all cases. It can thoroughly whiten teeth by eliminating stains deep in the enamel without damaging the enamel structure and causing any tissue toxicity. This study illustrates the superiority of aPDT for dental whitening and the approach to exploring carbon-dots-based nanostructures in the treatment of oral diseases.

Silver@Prussian Blue Core-Satellite Nanostructures as Multimetal Ions Switch for Potent Zero-Background SERS Bioimaging-Guided Chronic Wound Healing.

Metal-organic framework-based metal ion therapy has attracted increasing attention to promote the cascade wound-healing process. However, multimetal ion synergistic administration and accurately controlled ion release are still the challenges. Herein, an aptamer-functionalized silver@cupriferous Prussian blue (ACPA) is established as a metal-based theranostic nanoagent for a chronic nonhealing diabetic wound treatment. Prussian blue offers a programmable nanoplatform to formulate metal ion prescriptions, achieving cooperative wound healing. Silver, copper, and iron ions are released from ACPA controlled by the near-infrared-triggered mild hyperthermia and then synergistically participate in antipathogen, cell migration, and revascularization. ACPA also demonstrates a unique core-satellite nanostructure which enables it with improved surface-enhanced Raman scattering (SERS) capability as potent bacteria-targeted Raman-silent nanoprobe to monitor the residual bacteria during wound healing with nearly zero background. The theranostic feature of ACPA allows high-performance SERS imaging-guided chronic wound healing in infectious diabetic skin and keratitis.

Label-Free Surface-Enhanced Raman Scattering Bioanalysis Based on Au@Carbon Dot Nanoprobes.

Surface-enhanced Raman scattering (SERS) technology has attracted more and more attention in the biomedical field due to its ability to provide molecular fingerprint information of biological samples, as well as its potential in single-cell analysis. This work aims to establish a simple strategy for label-free SERS bioanalysis based on Au@carbon dot nanoprobes (Au@CDs). Here, polyphenol-derived CDs are utilized as the reductant to rapidly synthesize core-shell Au@CD nanostructures, which allows powerful SERS performance even when the concentration of methylene blue (MB) is as low as 10-9 M, due to the cooperative Raman enhancement mechanism. For bioanalysis, Au@CDs can serve as a unique SERS nanosensor to identify the cellular components of biosamples (e.g., cancer cells and bacteria). The molecular fingerprints from different species can be further distinguished after combination with the principal component analysis. In addition, Au@CDs also enable label-free SERS imaging to analyze intracellular composition profiles. This strategy offers a feasible, label-free SERS bioanalysis, opening up a new prospect for nanodiagnosis.

In situ photothermal nano-vaccine based on tumor cell membrane-coated black phosphorus-Au for photo-immunotherapy of metastatic breast tumors.

Cancer vaccines which can activate antitumor immune response have great potential for metastatic tumors treatment. However, clinical translation of cancer vaccines remained challenging due to weak tumor antigen immunogenicity, inefficient in vivo delivery, and immunosuppressive tumor microenvironment. Nanomaterials-based photothermal treatment (PTT) triggers immunogenic cell death while providing in situ tumor-associated antigens for subsequent anti-tumor immunity. Here, an in situ photothermal nano-vaccine (designated as BCNCCM) based on cancer cell membrane (CCM) was explored by co-encapsulating immune adjuvant CpG oligodeoxynucleotide (ODN) loaded black phosphorus-Au (BP-Au) nanosheets together with an indoleamine 2,3-dioxygenase (IDO) inhibitor (NLG919) by CCM, for the elimination of primary and metastatic breast tumors. The nano-vaccine could be delivered to tumor site selectively by CCM targeting and exhibit vaccine-like functions through the combined effect of in situ generated tumor-associate agents after PTT and immune adjuvant CpG, resulting in trigger of tumor-specific immunity. Furthermore, tumor inhibition was enhanced owing to the reversed immunosuppressive microenvironment mediated by IDO inhibitors. The nano-vaccine not only had good therapeutic effect on primary and metastatic tumors, but also could prevent tumor recurrence by producing systemic immune memory. Therefore, the photothermal nano-vaccine which coordinate in situ vaccine-like function and immune modulation may be a promising stragegy for photo-immunotherapy of metastatic tumors.

Mussel-inspired hydrogels for fast fabrication of flexible SERS tape for point-of-care testing of ß-blockers.

The flexible surface-enhanced Raman scattering (SERS) platform has ceaselessly propelled the development of point-of-care testing (POCT) in diverse fields. Herein, we report a facile strategy for the SERS-chemometric analysis of four ß-blockers (bisoprolol, metoprolol, acebutolol and esmolol) based on a super-sticky mussel-inspired hydrogel SERS tape. The surface morphology and mechanical properties of the hydrogel tape can be easily controlled by adjusting the compositional ratio. The optimized tape with excellent toughness and adhesiveness allows efficient collection of analytes through a simple "paste and peel off" approach, further by spraying with silver nanoparticles using a household sprayer to instantly assemble a flexible SERS substrate, the analytes can then detected by a portable Raman spectrometer. This POCT strategy enables the identification and discrimination of four similar ß-blockers with high sensitivity and accuracy in combination with the statistical algorithms. The developed SERS tape is finally utilized for the recognition of ß-blockers in simulated urine solution, which realizes a limit of detection of 1.0 ng mL-1, revealing a promising potential of this SERS-based POCT for the clinical detection of doping abuse.

NIR-II Responsive Molybdenum Dioxide Nanosystem Manipulating Cellular Immunogenicity for Enhanced Tumor Photoimmunotherapy.

Photothermal therapy (PTT) in the second near-infrared (NIR-II) window has emerged as a better candidate for deep-tissue tumor elimination. More interestingly, the photothermal ablated tumor cells also manifest somewhat immunostimulation potency to elicit antitumor immunity, although most dying cells are undergoing apoptosis that is commonly considered as immunologically silent. Here, a NIR-II responsive nanosystem is established for tumor photoimmunotherapy using molybdenum dioxide (MoO2) nanodumbbells as the nanoconverter. Meanwhile, an apoptosis-blocking strategy is proposed to regulate the cell death pattern under NIR-II laser irradiation in order to improve the immunogenic cell death. The nanoformulation can efficiently block caspase 8-dependent apoptotic pathway in photothermal ablated tumor cells and transform into more immunogenic death patterns, thereby activating systemic immunity to inhibit tumor growth and metastasis. In addition, this strategy also helps enhance the body's responses to α-PD-1 immune checkpoint inhibitor, which implies a potential optimal combination for cancer immunotherapy.

Carbon Dots with Intrinsic Bioactivities for Photothermal Optical Coherence Tomography, Tumor-Specific Therapy and Postoperative Wound Management.

Carbon dots (CDs) are considered as promising candidates with superior biocompatibilities for multimodel cancer theranostics. However, incorporation of exogenous components, such as targeting molecules and chemo/photo therapeutic drugs, is often required to improve the therapeutic efficacy. Herein, an "all-in-one" CDs that exhibit intrinsic bioactivities for bioimaging, potent tumor therapy, and postoperative management is proposed. The multifunctional CDs derived from gallic acid and tyrosine (GT-CDs) consist of a graphitized carbon core and N, O-rich functional groups, which endow them with a high near-infrared (NIR) photothermal conversion efficiency of 33.9% and tumor-specific cytotoxicity, respectively. A new imaging modality, photothermal optical coherence tomography, is introduced using GT-CDs as the contrast agent, offering the micrometer-scale resolution 3D tissue morphology of tumor. For cancer therapy, GT-CDs initiate the intracellular generation of reactive oxygen species in tumor cells but not normal cells, further induce the mitochondrial collapse and subsequent tumor cellular apoptosis. Combined with NIR photothermal treatment, synergistic antitumor therapy is achieved in vitro and in vivo. GT-CDs also promote the healing process of bacteria-contaminated skin wound, demonstrating their potential to prevent postoperative infection. The integrated theranostic strategy based on versatile GT-CDs supplies an alternative easy-to-handle pattern for disease management.

Dual-responsive ultrathin 1T-phase niobium telluride nanosheet-based delivery systems for enhanced chemo-photothermal therapy.

1T-phase niobium telluride (NbTe2) nanosheets are becoming increasingly important in emerging fields, such as spintronics, sensors and magneto-optoelectronics, due to their excellent physical and chemical properties. However, exploration on their biomedical applications are limited. Herein, ultrathin 1T-phase NbTe2 single-crystalline nanosheets with excellent photothermal performance, high drug-loading rate, near-infrared (NIR) light/acidic pH-triggered drug release, and low toxicity were developed for potentiated photothermal therapy. Importantly, they showed excellent biocompatibility in vivo and in vitro. NbTe2 nanosheets loaded with integrated stress response inhibitors (ISRIB) could achieve chemo-photothermal therapy of tumors through the ATF4-ASNS signaling axis. Ultrathin 1T-phase NbTe2 single-crystalline nanosheets with unique photothermal properties, drug loading rate and safety provide dramatic possibilities in biomedical applications, such as tissue imaging, photothermal therapeutics and pharmaceutics.

Quantitative label-free optical technique to analyze the ultrastructure changes and spatiotemporal relationship of enamel induced by Msx2 deletion.

New advances in the molecular mechanism of enamel mineralization reveal the practical significance of regenerative medicine in clinical transformation. Muscle segment homeobox 2 (MSX2), a transcription factor, is recently reported to be closely associated with the amelogenesis imperfecta (AI). To elucidate the biomineralization framework of AI enamel, herein, Msx2 gene mutant mice are investigated by dual-mode noninvasive spectroscopic analytical techniques for the first time. Optical coherence tomography (OCT) records the depth-resolved structural information of mice teeth, where a dramatic decrease in enamel thickness and quality occurred in Msx2 deficient (Msx2-/- ) enamel. And it has the advantages of fast, noninvasive and low cost. Raman spectroscopy, a powerful molecular fingerprint tool, further witnesses an imbalance of inorganic and organic contents in Msx2-/- enamel. In addition, abnormal expression of MSX2 also influences the spatial distribution of phosphate in enamel according to the Raman spectral imaging. Therefore, OCT integrated with Raman spectroscopy provides the quantitative label-free optical parameters of both the physical structure and chemical component in mice enamel, which strengthens the understanding of the biomineralization process underlying the Msx2-related amelogenesis imperfect.

Redox responsive nanoparticle encapsulating black phosphorus quantum dots for cancer theranostics.

Effective cancer treatment puts high demands for cancer theranostics. For cancer diagnostics, optical coherence tomography (OCT) technology (including photothermal optical coherence tomography (PT-OCT)) has been widely investigated since it induces changes in optical phase transitions in tissue through environmental changes (such as temperature change for PT-OCT). In this report, redox responsive nanoparticle encapsulating black phosphorus quantum dots was developed as a robust PT-OCT agent. Briefly, black phosphorus quantum dots (BPQDs) are incorporated into cysteine-based poly-(disulfide amide) (Cys-PDSA) to form stable and biodegradable nanoagent. The excellent photothermal feature allows BPQD/Cys-PDSA nanoparticles (NPs) as a novel contrast agent for high-resolution PT-OCT bioimaging. The Cys-PDSA can rapidly respond to glutathione and effectively release BPQDs and drugs in vitro and in vivo. And the obtained NPs exhibit excellent near-infrared (NIR) photothermal transduction efficiency and drug delivery capacity that can serve as novel therapeutic platform, with very low chemo drug dosage and side effects. Both of the polymer and BPQD are degradable, indicating this platform is a rare PT-OCT agent that is completely biodegradable. Overall, our research highlights a biodegradable and biocompatible black phosphorus-based nanoagent for both cancer diagnosis and therapy.

Strontium-substituted sub-micron bioactive glasses inhibit ostoclastogenesis through suppression of RANKL-induced signaling pathway.

Strontium-substituted bioactive glass (Sr-BG) has shown superior performance in bone regeneration. Sr-BG-induced osteogenesis has been extensively studied; however, Sr-BG-mediated osteoclastogenesis and the underlying molecular mechanism remain unclear. It is recognized that the balance of osteogenesis and osteoclastogenesis is closely related to bone repair, and the receptor activators of nuclear factor kappaB ligand (RANKL) signaling pathway plays a key role of in the regulation of osteoclastogenesis. Herein, we studied the potential impact and underling mechanism of strontium-substituted sub-micron bioactive glass (Sr-SBG) on RANKL-induced osteoclast activation and differentiation in vitro. As expected, Sr-SBG inhibited RANKL-mediated osteoclastogenesis significantly with the experimental performance of decreased mature osteoclasts formation and downregulation of osteoclastogenesis-related gene expression. Furthermore, it was found that Sr-SBG might suppress osteoclastogenesis by the combined effect of strontium and silicon released through inhibition of RANKL-induced activation of p38 and NF-κB pathway. These results elaborated the effect of Sr-SBG-based materials on osteoclastogenesis through RANKL-induced downstream pathway and might represent a significant guidance for designing better bone repair materials.

Photo-induced synthesis of molybdenum oxide quantum dots for surface-enhanced Raman scattering and photothermal therapy.

By means of a simple and photo-induced method, four colors of molybdenum oxide quantum dots (MoOx QDs) have been synthesized, using Mo(CO)6 as the structural guiding agent and molybdenum source. The as-prepared MoOx QDs display diverse optical properties due to the different configurations of oxygen vacancies in various nanostructures. Among them, crystalline molybdenum dioxide (MoO2) with a deep blue color shows the most intense localized surface plasmon resonance effect in the near-infrared (NIR) region. The strong NIR absorption endows MoO2 QDs with a high photothermal conversion efficiency of 66.3%, enabling broad prospects as a photo-responsive nanoagent for photothermal therapy of cancer. Moreover, MoO2 QDs can also serve as a novel semiconductor substrate for ultrasensitive surface-enhanced Raman scattering (SERS) analysis of aromatic molecules, amino acids and antibiotics, with SERS performance comparable to that of noble metal-based substrates. The therapeutic applications of MoO2 QDs open up a new avenue for tumor nanomedicine.

SERS analysis of carcinoma-associated fibroblasts in a tumor microenvironment based on targeted 2D nanosheets.

Carcinoma-associated fibroblasts (CAFs), one of the most important components of a tumor microenvironment (TME), play a significant role in the complex tumorigenesis process. Herein, the evolution of CAFs in TME is elaborately investigated by surface-enhanced Raman spectroscopy (SERS), a molecular fingerprint technique. Two-dimensional (2D) nanocomposites consisting of gold nanoparticles and a supramolecular "PCsheet" self-assembled between 2D nanosheets and oxidized phosphatidylcholine (PC) are fabricated as SERS-active probes to specifically recognize the CD36 receptor on the cytomembrane of the fibroblasts, a reliable landmark of CAF development. The 2D SERS substrates can also illuminate the fingerprint information around the CD36 protein with high detection sensitivity, which helps elucidate the biochemical component transition in the protein mini-domain during carcinoma progression. Visualized data are then supplied by label-free SERS imaging to exploit the distribution of biomolecules on the plasma membrane. In addition, the repressed expression of CD36 in TME is detected in lung metastasis tumor-bearing mice. This study based on the 2D SERS technique opens up an alternative avenue for unveiling carcinoma-associated molecular events.

Hydrophobic carbon dots with blue dispersed emission and red aggregation-induced emission.

Carbon dots (CDs) have been studied for years as one of the most promising fluorescent nanomaterials. However, CDs with red or solid-state fluorescence are rarely reported. Herein, through a one-pot solvothermal treatment, hydrophobic CDs (H-CDs) with blue dispersed emission and red aggregation-induced emission are obtained. When water is introduced, the hydrophobic interaction leads to aggregation of the H-CDs. The formation of H-CD clusters induces the turning off of the blue emission, as the carbonized cores suffer from π-π stacking interactions, and the turning on of the red fluorescence, due to restriction of the surfaces' intramolecular rotation around disulfide bonds, which conforms to the aggregation-induced-emission phenomenon. This on-off fluorescence of the H-CDs is reversible when the H-CD powder is completely dissolved. Moreover, the H-CD solution dispersed in filter paper is nearly colorless. Finally, we develop a reversible two switch-mode luminescence ink for advanced anti-counterfeiting and dual-encryption.

Biodegradable Black Phosphorus-based Nanomaterials in Biomedicine: Theranostic Applications.

Ascribe to the unique two-dimensional planar nanostructure with exceptional physical and chemical properties, black phosphorous (BP) as the emerging inorganic twodimensional nanomaterial with high biocompatibility and degradability has been becoming one of the most promising materials of great potentials in biomedicine. The exfoliated BP sheets possess ultra-high surface area available for valid bio-conjugation and molecular loading for chemotherapy. Utilizing the intrinsic near-infrared optical absorbance, BPbased photothermal therapy in vivo, photodynamic therapy and biomedical imaging has been realized, achieving unprecedented anti-tumor therapeutic efficacy in animal experiments. Additionally, the BP nanosheets can strongly react with oxygen and water, and finally degrade to non-toxic phosphate and phosphonate in the aqueous solution. This manuscript aimed to summarize the preliminary progresses on theranostic application of BP and its derivatives black phosphorus quantum dots (BPQDs), and discussed the prospects and the state-of-art unsolved critical issues of using BP-based material for theranostic applications.

A two-dimensional fingerprint nanoprobe based on black phosphorus for bio-SERS analysis and chemo-photothermal therapy.

Flake-shaped nanohybrids based on black phosphorus (BP) have been developed as multifunctional theranostic nanoplatforms for drug delivery, phototherapy and bioimaging. In this work, we report a facile strategy for fabrication of black phosphorus-Au nanoparticle hybrids (BP-AuNPs), which reveal an extraordinary near-infrared (NIR) photothermal transduction efficiency and drug delivery capacity. The applications of the nanocomposites as therapeutic agents for high-performance chemo-photothermal tumor therapy are accomplished in vitro and in vivo. BP-AuNPs also exhibit wonderful surface-enhanced Raman scattering (SERS) activity under NIR laser excitation with a low Raman background, allowing BP-AuNPs to be used as a promising two-dimensional (2D) fingerprint nanoprobe for bio-SERS analysis. The cellular component identification and label-free live-cell bioimaging based on this type of 2D SERS substrate are generally investigated, which open up promising new perspectives in nanomedicine, including diagnosis, imaging and therapy.

Investigating the autophagy pathway in silver@gold core-shell nanoparticles-treated cells using surface-enhanced Raman scattering.

Previous studies have shown that nanoparticles can induce autophagy, and the main approach for investigating autophagy induced by nanoparticles is via traditional methods such as TEM and biochemical assay. These methods measurements suffer from the disadvantages of complicated experimental processes, cell destruction, as well as lack of characterization of individual stages of the autophagy pathway. Surface-enhanced Raman scattering (SERS) has been extensively used in biological applications. With the combination of SERS and chemometric methods, such as principal component analysis-linear discriminant analysis (PCA-LDA), identification and distribution mapping of endosomes and lysosomes in the endocytosis of Au nanoparticles has been achieved by segregating the spectra from complex SERS data sets in the previous study. In this study, silver@gold core-shell nanoparticles (Ag@Au NPs) were synthesized by reduction of gold ions on the surface of the silver nanoparticles, and the autophagy induced by Ag@Au NPs was studied with Ag@Au NPs serving both as an autophagy inducer and as a high-performance SERS substrate. Pro-survival autophagy induced by Ag@Au NPs was proved by the western blot assay, flow cytometry and fluorescent staining. Furthermore, the autophagy pathway in Ag@Au NPs-treated cells was first elucidated by SERS combined with a modified reference-based PCA-LDA methodology. This study provides a feasible way of using SERS to elucidate the autophagy pathway induced by nanoparticles.

Effect of Red Light-Emitting Diodes Irradiation on Hemoglobin for Potential Hypertension Treatment Based on Confocal Micro-Raman Spectroscopy.

Red light-emitting diodes (LED) were used to irradiate the isolated hypertension hemoglobin (Hb) and Raman spectra difference was recorded using confocal micro-Raman spectroscopy. Differences were observed between the controlled and irradiated Hb by comparing the spectra records. The Raman spectrum at the 1399 cm-1 band decreased following prolonged LED irradiation. The intensity of the 1639 cm-1 band decreased dramatically in the first five minutes and then gradually increased in a time-dependent manner. This observation indicated that LED irradiation increased the ability of oxygen binding in Hb. The appearance of the heme aggregation band at 1399 cm-1, in addition to the oxygen marker band at 1639 cm-1, indicated that, in our study, 30 min of irradiation with 15.0 mW was suitable for inhibiting heme aggregation and enhancing the oxygen-carrying capacity of Hb. Principal component analysis showed a one-to-one relationship between irradiated Hb at different time points and the corresponding Raman spectra. Our approach could be used to analyze the hemoglobin from patients with confocal micro-Raman spectroscopy and is helpful for developing new nondrug hypertension therapy.

Synthesis of Au NP@MoS2 Quantum Dots Core@Shell Nanocomposites for SERS Bio-Analysis and Label-Free Bio-Imaging.

In this work, we report a facile method using MoS2 quantum dots (QDs) as reducers to directly react with HAuCl4 for the synthesis of Au nanoparticle@MoS2 quantum dots (Au NP@MoS2 QDs) core@shell nanocomposites with an ultrathin shell of ca. 1 nm. The prepared Au NP@MoS2 QDs reveal high surface enhanced Raman scattering (SERS) performance regarding sensitivity as well as the satisfactory SERS reproducibility and stability. The limit of detection of the hybrids for crystal violet can reach 0.5 nM with a reasonable linear response range from 0.5 µM to 0.5 nM (R² ≈ 0.974). Furthermore, the near-infrared SERS detection based on Au NP@MoS2 QDs in living cells is achieved with distinct Raman signals which are clearly assigned to the various cellular components. Meanwhile, the distinguishable SERS images are acquired from the 4T1 cells with the incubation of Au NP@MoS2 QDs. Consequently, the straightforward strategy of using Au NP@MoS2 QDs exhibits great potential as a superior SERS substrate for chemical and biological detection as well as bio-imaging.

Multifunctional Nanoplatform Based on Black Phosphorus Quantum Dots for Bioimaging and Photodynamic/Photothermal Synergistic Cancer Therapy.

A multifunctional nanoplatform based on black phosphorus quantum dots (BPQDs) was developed for cancer bioimaging and combined photothermal therapy (PTT) and photodynamic therapy (PDT). BPQDs were functionalized with PEG chains to achieve improved biocompatibility and physiological stability. The as-prepared nanoparticles exhibite prominent near-infrared (NIR) photothermal and red-light-triggered photodynamic properties. The combined therapeutic application of PEGylated BPQDs were then performed in vitro and in vivo. The results demonstrate that the combined phototherapy significantly promote the therapeutic efficacy of cancer treatment in comparison with PTT or PDT alone. BPQDs could also serve as the loading platform for fluorescent molecules, allowing reliable imaging of cancer cells. In addition, the low cytotoxicity and negligible side effects to main organs were observed in toxicity experiments. The theranostic characteristics of PEGylated BPQDs provide an uplifting potential for the future clinical applications.