Clinically Translatable Solid-State Dye for NIR-II Imaging of Medical Devices.

Medical devices are commonly implanted underneath the skin, but how to real-time noninvasively monitor their migration, integrity, and biodegradation in human body is still a formidable challenge. Here, the study demonstrates that benzyl violet 4B (BV-4B), a main component in the FDA-approved surgical suture, is found to produce fluorescence signal in the first near-infrared window (NIR-I, 700-900 nm) in polar solutions, whereas BV-4B self-assembles into highly crystalline aggregates upon a formation of ultrasmall nanodots and can emit strong fluorescence in the second near-infrared window (NIR-II, 1000-1700 nm) with a dramatic bathochromic shift in the absorption spectrum of ≈200 nm. Intriguingly, BV-4B-involved suture knots underneath the skin can be facilely monitored during the whole degradation process in vivo, and the rupture of the customized BV-4B-coated silicone catheter is noninvasively diagnosed by NIR-II imaging. Furthermore, BV-4B suspended in embolization glue achieves hybrid fluorescence-guided surgery (hybrid FGS) for arteriovenous malformation. As a proof-of-concept study, the solid-state BV-4B is successfully used for NIR-II imaging of surgical sutures in operations of patients. Overall, as a clinically translatable solid-state dye, BV-4B can be applied for in vivo monitoring the fate of medical devices by NIR-II imaging.

Molecularly Engineered Room-Temperature Phosphorescence for Biomedical Application: From the Visible toward Second Near-Infrared Window.

Phosphorescence, characterized by luminescent lifetimes significantly longer than that of biological autofluorescence under ambient environment, is of great value for biomedical applications. Academic evidence of fluorescence imaging indicates that virtually all imaging metrics (sensitivity, resolution, and penetration depths) are improved when progressing into longer wavelength regions, especially the recently reported second near-infrared (NIR-II, 1000-1700 nm) window. Although the emission wavelength of probes does matter, it is not clear whether the guideline of "the longer the wavelength, the better the imaging effect" is still suitable for developing phosphorescent probes. For tissue-specific bioimaging, long-lived probes, even if they emit visible phosphorescence, enable accurate visualization of large deep tissues. For studies dealing with bioimaging of tiny biological architectures or dynamic physiopathological activities, the prerequisite is rigorous planning of long-wavelength phosphorescence, being aware of the cooperative contribution of long wavelengths and long lifetimes for improving the spatiotemporal resolution, penetration depth, and sensitivity of bioimaging. In this Review, emerging molecular engineering methods of room-temperature phosphorescence are discussed through the lens of photophysical mechanisms. We highlight the roles of phosphorescence with emission from visible to NIR-II windows toward bioapplications. To appreciate such advances, challenges and prospects in rapidly growing studies of room-temperature phosphorescence are described.

Degradable Fe3O4-based nanocomposite for cascade reaction-enhanced anti-tumor therapy.

Cascade catalytic therapy has been recognized as a promising cancer treatment strategy, which is due in part to the induced tumor apoptosis when converting intratumoral hydrogen peroxide (H2O2) into highly toxic hydroxyl radicals (˙OH) based on the Fenton or Fenton-like reactions. Moreover this is driven by the efficient catalysis of glucose oxidization associated with starving therapy. The natural glucose oxidase (GO x ), recognized as a "star" enzyme catalyst involved in cancer treatment, can specially and efficiently catalyze the glucose oxidization into gluconic acid and H2O2. Herein, pH-responsive biodegradable cascade therapeutic nanocomposites (Fe3O4/GO x -PLGA) with dual enzymatic catalytic features were designed to respond to the tumor microenvironment (TME) and to catalyze the cascade reaction (glucose oxidation and Fenton-like reaction) for inducing oxidase stress. The GO x -motivated oxidation reaction could effectively consume intratumoral glucose to produce H2O2 for starvation therapy and the enriched H2O2 was subsequently converted into highly toxic ˙OH by a Fe3O4-mediated Fenton-like reaction for chemodynamic therapy (CDT). In addition, the acidity amplification owing to the generation of gluconic acid will in turn accelerate the degradation of the nanocomposite and initiate the Fe3O4-H2O2 reaction for enhancing CDT. The resultant cooperative cancer therapy was proven to provide highly efficient tumor inhibition on HeLa cells with minimal systemic toxicity. This cascade catalytic Fenton nanocomposite might provide a promising strategy for efficient cancer therapy.

Design strategies and applications of smart optical probes in the second near-infrared window.

Over the last decade, a series of synergistic advances in the synthesis chemistries and imaging instruments have largely boosted a significant revolution, in which large-scale biomedical applications are now benefiting from optical bioimaging in the second near-infrared window (NIR-II, 1000-1700 nm). The large tissue penetration and limited autofluorescence associated with long-wavelength imaging improve translational potential of NIR-II imaging over common visible-light (400-650 nm) and NIR-I (750-900 nm) imaging, with ongoing profound effects on the studies of precision medicine. Unfortunately, the majority of NIR-II probes are designed as "always-on" luminescent imaging contrasts, continuously generating unspecific signals regardless of whether they reach pathological locations. Thus, in vivo imaging by traditional NIR-II probes usually suffers from weak detect precision due to high background noise. In this context, the advances of optical imaging now enter into an era of precise control of NIR-II photophysical kinetics. Developing NIR-II optical probes that can efficiently activate their luminescent signal in response to biological targets of interest and substantially suppress the background interferences have become a highly prospective research frontier. In this review, the merits and demerits of optical imaging probes from visible-light, NIR-I to NIR-II windows are carefully discussed along with the lens of stimuli-responsive photophysical kinetics. We then highlight the latest development in engineering methods for designing smart NIR-II optical probes. Finally, to appreciate such advances, challenges and prospect in rapidly growing study of smart NIR-II probes are addressed in this review.

Emerging single-atom iron catalysts for advanced catalytic systems.

Due to the elusive structure-function relationship, traditional nanocatalysts always yield limited catalytic activity and selectivity, making them practically difficult to replace natural enzymes in wide industrial and biomedical applications. Accordingly, single-atom catalysts (SACs), defined as catalysts containing atomically dispersed active sites on a support material, strikingly show the highest atomic utilization and drastically boosted catalytic performances to functionally mimic or even outperform natural enzymes. The molecular characteristics of SACs (e.g., unique metal-support interactions and precisely located metal sites), especially single-atom iron catalysts (Fe-SACs) that have a similar catalytic structure to the catalytically active center of metalloprotease, enable the accurate identification of active centers in catalytic reactions, which afford ample opportunity for unraveling the structure-function relationship of Fe-SACs. In this review, we present an overview of the recent advances of support materials for anchoring an atomic dispersion of Fe. Subsequently, we highlight the structural designability of support materials as two sides of the same coin. Moreover, the applications described herein illustrate the utility of Fe-SACs in a broad scope of industrially and biologically important reactions. Finally, we present an outlook of the major challenges and opportunities remaining for the successful combination of single Fe atoms and catalysts.

Engineering single-atom catalysts toward biomedical applications.

Due to inherent structural defects, common nanocatalysts always display limited catalytic activity and selectivity, making it practically difficult for them to replace natural enzymes in a broad scope of biologically important applications. By decreasing the size of the nanocatalysts, their catalytic activity and selectivity will be substantially improved. Guided by this concept, the advances of nanocatalysts now enter an era of atomic-level precise control. Single-atom catalysts (denoted as SACs), characterized by atomically dispersed active sites, strikingly show utmost atomic utilization, precisely located metal centers, unique metal-support interactions and identical coordination environments. Such advantages of SACs drastically boost the specific activity per metal atom, and thus provide great potential for achieving superior catalytic activity and selectivity to functionally mimic or even outperform natural enzymes of interest. Although the size of the catalysts does matter, it is not clear whether the guideline of "the smaller, the better" is still correct for developing catalysts at the single-atom scale. Thus, it is clearly a new, urgent issue to address before further extending SACs into biomedical applications, representing an important branch of nanomedicine. This review begins by providing an overview of recent advances of synthesis strategies of SACs, which serve as a basis for the discussion of emerging achievements in improving the enzyme-like catalytic properties at an atomic level. Then, we carefully compare the structures and functions of catalysts at various scales from nanoparticles, nanoclusters, and few-atom clusters to single atoms. Contrary to conventional wisdom, SACs are not the most catalytically active catalysts in specific reactions, especially those requiring multi-site auxiliary activities. After that, we highlight the unique roles of SACs toward biomedical applications. To appreciate these advances, the challenges and prospects in rapidly growing studies of SACs-related catalytic nanomedicine are also discussed in this review.

A phosphorescent probe for in vivo imaging in the second near-infrared window.

In the second near-infrared spectral window (NIR-II; with wavelengths of 1,000-1,700 nm), in vivo fluorescence imaging can take advantage of reduced tissue autofluorescence and lower light absorption and scattering by tissue. Here, we report the development and in vivo application of a NIR-II phosphorescent probe that has lifetimes of hundreds of microseconds and a Stokes shift of 430 nm. The probe is made of glutathione-capped copper-indium-selenium nanotubes, and in acidic environments (pH 5.5-6.5) switches from displaying fluorescence to phosphorescence. In xenograft models of osteosarcoma and breast cancer, intravenous or intratumoral injections of the probe enabled phosphorescence imaging at signal-to-background ratios, spatial resolutions and sensitivities higher than NIR-II fluorescence imaging with polymer-stabilized copper-indium-sulfide nanorods. Phosphorescence imaging may offer superior imaging performance for a range of biomedical uses.

Nanoprobe-mediated precise imaging and therapy of glioma.

Gliomas are the most common primary brain tumors in adults, accounting for 80% of primary intracranial tumors. Due to the heterogeneous and infiltrating nature of malignant gliomas and the hindrance of the blood-brain barrier (BBB), it is very difficult to accurately image and differentiate the malignancy grade of gliomas, thus significantly influencing the diagnostic accuracy and subsequent surgery or therapy. In recent years, the rapid development of emerging nanoprobes has provided a promising opportunity for the diagnosis and treatment of gliomas. After rational component regulation and surface modification, functional nanoprobes could efficiently cross the BBB, target gliomas, and realize single-modal or multimodal imaging of gliomas with high clarity. Moreover, these contrast nanoagents could also be conjugated with therapeutic drugs and cure cancerous tissues at the same time. Herein, we focus on the design strategies of nanoprobes for effective crossing of the BBB, and introduce the recent advances in the precise imaging and therapy of gliomas using functional nanoprobes. Finally, we also discuss the challenges and future directions of nanoprobe-based diagnosis and treatment of gliomas.

Ultrasmall copper nanoclusters with multi-enzyme activities.

Reactive oxygen species (ROS) as a key messenger of signal transduction mediate physiological activities, however, oxidative stress produced by excessive ROS can cause the destruction of cell homeostasis, which will result in a series of diseases. Therefore, effective control of ROS level is critical to the homeostasis of the cell. Here, we reported that glutathione (GSH)-stabilized copper nanoclusters (CuNCs) with about 9 Cu atoms can functionally mimic three major antioxidant enzymes, namely catalase (CAT), glutathione peroxidase (GPx) and superoxide dismutase (SOD). The rate of H2O2 decomposition was calculated to be ∼0.23 mg L-1 s-1 when the concentration of CuNCs was 100 µg mL-1. The SOD-like activity by catalyzing the disproportionation of superoxide to H2O2 and O2 reached 25.6 U mg-1 when the effective inhibition rate was ∼55.4%. Intracellular ROS scavenging studies further identified that CuNCs can obviously protect cells from oxidative stress and the cell viability recovered to above 90%. Hence, we expect that ultrasmall CuNCs will provide good therapeutic potential in the future treatment of ROS-related diseases.

Highly fluorescent copper nanoclusters for sensing and bioimaging.

Metal nanoclusters (NCs), typically consisting of a few to tens of metal atoms, bridge the gap between organometallic compounds and crystalline metal nanoparticles. As their size approaches the Fermi wavelength of electrons, metal NCs exhibit discrete energy levels, which in turn result in the emergence of intriguing physical and chemical (or physicochemical) properties, especially strong fluorescence. Compared with noble metals, copper is a relatively earth-abundant and cost-effective metal. Theoretical and experimental studies have shown that copper NCs (CuNCs) possess unique photoluminescent properties. To highlight these achievements, this review begins by providing an overview of a multitude of factors that play central roles in the fluorescence of CuNCs. Additionally, a critical perspective of how the aggregation of CuNCs can efficiently improve the florescent stability, tunability and intensity is also discussed. Following, we present representative applications of CuNCs in detection and in-vivo/in-vitro imaging and point out that in-situ generation of CuNCs for sensing and bioimaging may be an entry point for the in-depth studies of CuNCs as an intriguing probe. Finally, we outline current challenges and our perspective on the development of CuNCs.

Temperature-responsive iron nanozymes based on poly(N-vinylcaprolactam) with multi-enzyme activity.

Iron (Fe)-based nanozymes are widely applied in the biomedical field due to their enzyme-like catalytic activity. Herein, Fe(ii)-based coordination polymer nanohydrogels (FeCPNGs) have been conveniently prepared as a new type of nanozyme by the chelation reaction between ferrous iron and polymer nanohydrogels. The P(VCL-co-NMAM) nanohydrogels prepared by a reflux precipitation polymerization method using N-vinylcaprolactam (VCL) and N-methylol acrylamide (NMAM) as monomers and N,N-methylenebisacrylamide (MBA) as a crosslinker were esterified using P2O5 and then chelated with Fe(ii) ions to form nanozymes with peroxidase and superoxide dismutase (SOD) activity. It was found by dynamic light scattering (DLS) and transmission electron microscopy (TEM) that the nanohydrogels prepared with a monomer concentration of 4% and mass ratio of 1 : 1 (VCL : NMAM) had more uniform particle size, better dispersion and a distinct temperature response. The results of Fourier transform infrared (FTIR), DLS, TEM, X-ray powder diffraction (XRD) and X-ray photoelectron spectroscopy (XPS) indicated the successful preparation of the esterified nanohydrogel and FeCPNGs. Of particular importance is that such FeCPNGs can functionally mimic two antioxidant enzymes (peroxidase and superoxide dismutase) by UV analysis of catalytic oxidation between 3,3,5,5-tetramethylbenzidine (TMB) and H2O2 and the kit analysis of SOD-like activity.

Excretable Lanthanide Nanoparticle for Biomedical Imaging and Surgical Navigation in the Second Near-Infrared Window.

Recently, various second near-infrared window (NIR-II, 1000-1700 nm) fluorophores have been synthesized for in vivo imaging with nonradiation, high resolution, and low autofluorescence. However, most of the NIR-II fluorophores, especially inorganic nanoprobes, are mainly retained in the reticuloendothelial system (RES) such as the liver and spleen, leading to long-term safety concerns. Herein, a type of lanthanide-based excretable NIR-II nanoparticle, RENPs@Lips, which can be quickly cleared out of body after intravenous administration with half-lives of 23.0 h for the liver and 14.9 h for the spleen, is reported. Interestingly, over 90% of RENPs@Lips can be excreted through a hepatobiliary system within 72 h postinjection. The moderate blood half-time (T 1/2 = 17.96 min) allows for multifunctional applications in delineating the hemodynamics of vascular disorders (artery thrombosis, ischemia, and tumor angiogenesis) and monitoring blood perfusion in response to acute ischemia. In addition, RENPs@Lips exhibit high performance in identifying orthotopic tumor vessels intraoperatively and embolization surgery under NIR-II imaging navigation. Moreover, excellent signal-to-background ratio (SBR) is successfully achieved to facilitate sentinel lymph nodes biopsy (SLNB) with tumor-bearing mice. The high biocompatibility, favorable excretability, and outstanding optical properties warrant RENPs@Lips as novel promising NIR-II nanoparticles for future applications and translation into an interdisciplinary amalgamation of research in diverse fields.

Smart Polymers with Special Wettability.

Surface wettability plays a key role in addressing issues ranging from basic life activities to our daily life, and thus being able to control it is an attractive goal. Learning from nature, both of its structure and function, brings us much inspiration in designing smart polymers to tackle this major challenge. Life functions particularly depend on biomolecular recognition-induced interfacial properties from the aqueous phase onto either "soft" cell and tissue or "hard" inorganic bone and tooth surfaces. The driving force is noncovalent weak interactions rather than strong covalent combinations. An overview is provided of the weak interactions that perform vital actions in mediating biological processes, which serve as a basis for elaborating multi-component polymers with special wettabilities. The role of smart polymers from molecular recognitions to macroscopic properties are highlighted. The rationale is that highly selective weak interactions are capable of creating a dynamic synergetic communication in the building components of polymers. Biomolecules could selectively induce conformational transitions of polymer chains, and then drive a switching of physicochemical properties, e.g., roughness, stiffness and compositions, which are an integrated embodiment of macroscopic surface wettabilities.

Dynamic biointerfaces: from recognition to function.

The transformation of recognition signals into regulating macroscopic behaviors of biological entities (e.g., biomolecules and cells) is an extraordinarily challenging task in engineering interfacial properties of artificial materials. Recently, there has been extensive research for dynamic biointerfaces driven by biomimetic techniques. Weak interactions and chirality are two crucial routes that nature uses to achieve its functions, including protein folding, the DNA double helix, phospholipid membranes, photosystems, and shell and tooth growths. Learning from nature inspires us to design dynamic biointerfaces, which usually take advantage of highly selective weak interactions (e.g., synergetic chiral H-bonding interactions) to tailor their molecular assemblies on external stimuli. Biomolecules can induce the conformational transitions of dynamic biointerfaces, then drive a switching of surface characteristics (topographic structure, wettability, etc.), and eventually achieve macroscopic functions. The emerging progresses of dynamic biointerfaces are reviewed and its role from molecular recognitions to biological functions highlighted. Finally, a discussion is presented of the integration of dynamic biointerfaces with the basic biochemical processes, possibly solving the big challenges in life science.

Redox- and temperature-controlled drug release from hollow mesoporous silica nanoparticles.

A controlled drug-delivery system has been developed based on mesoporous silica nanoparticles that deliver anticancer drugs into cancer cells with minimized side effects. The copolymer of two oligo(ethylene glycol) macromonomers cross-linked by the disulfide linker N,N'-bis(acryloyl)cystamine is used to cap hollow mesoporous silica nanoparticles (HMSNs) to form a core/shell structure. The HMSN core is applied as a drug storage unit for its high drug loading capability, whereas the polymer shell is employed as a switch owing to its redox/temperature dual responses. The release behavior in vitro of doxorubicin demonstrated that the loaded drugs could be released rapidly at higher temperature or in the presence of glutathione (GSH). Thus, the dual-stimulus polymer shell exhibiting a volume phase transition temperature higher than 37 °C can effectively avoid drug leakage in the bloodstream owing to the swollen state of the shell. Once internalized into cells, the carriers shed the polymer shell because of cleavage of the disulfide bonds by GSH, which results in the release of the loaded drugs in cytosol. This work may prove to be a significant development in on-demand drug release systems for cancer therapy.

Silica composite nanoparticles containing fluorescent solid core and mesoporous shell with different thickness as drug carrier.

Nonporous silica transitional approach was employed to create core-shell architectural nanocomposites, which performed particularly well in morphology and controllable synthesis. The silica nanocomposites containing fluorescent solid SiO2 core and mesoporous silica shell (F-nSiO2/mSiO2) presented distinct structures of narrow size distribution, stable and shell thickness independent fluorescence, and high specific surface area. Furthermore, the thickness of mesoporous shell could be precisely tailored by the amount of TEOS and solid SiO2 seeds. Drug delivery study of F-nSiO2/mSiO2 with different mesoporous thicknesses were carried out, and Peppas equation was adopted to demonstrate the controlled releasing mechanism of doxorubicin (DOX). The diffusion rate of DOX from F-nSiO2/mSiO2 nanocomposites depended on the thickness of mesoporous shell and electrostatic interaction between drug and silanol group, which facilitated an enhanced drug releasing activity at pH 5.5 than 7.4. What's more, particles loaded DOX showed similar cytotoxicity compared with pure DOX, while no obvious cytotoxicity of carrier was observed in MTT tests for blank particles. These characteristics mentioned above implied that core/shell structured F-nSiO2/mSiO2 had a great potential for controlled drug delivery system.

Poly(vinylcaprolactam)-based biodegradable multiresponsive microgels for drug delivery.

Poly(vinylcaprolactam) (PVCL)-based biodegradable microgels were prepared for the biomedical application as drug delivery system via precipitation polymerization, where N,N-bis(acryloyl) cystamine (BAC) served as cross-linker, methacrylic acid (MAA) and polyethylene glycol (PEG) methyl ether methacrylate acted as comonomers. The microgels with excellent stability had distinct temperature sensitivity as largely observed in the case of PVCL-based particles and their volume phase transition temperature (VPTT) shifted to higher temperature with increasing MAA content and ambient pH. In the presence of reducing agent glutathione (GSH) or dithiothreitol (DTT), the microgels could be degraded into individual linear polymer chains by the cleavage of the disulfide linkages coming from the cross-linker BAC. The microgels could effectively encapsulate Doxorubicin (DOX) inside and presented stimuli-triggered drug release in acidic or reducing environment. The results of the cytotoxicity assays further demonstrated that the blank microgels were nontoxic to normal cells while DOX-loaded microgels presented efficient antitumor activity to HeLa cells.

In vivo distribution and antitumor activity of doxorubicin-loaded N-isopropylacrylamide-co-methacrylic acid coated mesoporous silica nanoparticles and safety evaluation.

The objective of this study was to develop and evaluate the antitumor activity and the safety of a delivery system containing mesoporous silica nanoparticles (MSN) coated with pH-responsive poly (N-isopropylacrylamide-co-methacrylic acid; P NIPAM-co-MAA) for doxorubicin (DOX) delivery (P-MSN-DOX) in vitro and in vivo. We reported that P-MSN-DOX nanoparticles (190 ± 30 nm) offered a DOX-loading coefficient of more than 20%. DOX release from the P-MSN-DOX formulation was pH-dependent with enhanced antitumor effects in vitro compared with traditional MSN-DOX, which was weakly cytotoxic due to negligible drug release at tested pHs. P-MSN-DOX circulated longer, with less cardiac and renal accumulation as shown by pharmacokinetics and biodistribution studies in vivo. Also, the P-MSN-DOX delivery system had greater antitumor activity in mice bearing a murine sarcoma S-180 cell line. This finding was correlated with both in vitro and in vivo. Subacute toxicity tests revealed a low P-MSN-DOX toxicity in vivo, as well. Thus, P-MSN-DOX appears to be an efficacious and safe cancer treatment strategy.

pH-responsive composite microspheres based on magnetic mesoporous silica nanoparticle for drug delivery.

pH-responsive composite microspheres, consisting of a core of Fe3O4 nanoparticle, a sandwiched layer of mesoporous silica and a shell of crosslinked poly (methacrylic acid) (PMAA), were successfully synthesized via distillation precipitation polymerization. The pKa of the composite microsphere increased with the increase in the crosslinking density. Doxorubicin hydrochloride (DOX) was applied as a model drug, and the behavior of drug storage/release was investigated. The cumulative release of DOX-loaded composite microsphere in vitro showed that the drug release rate was much faster below its pKa than that of above its pKa. Because pH of most tumor tissues was lower than that of normal tissues, the pH-responsive composite microspheres are promising drug delivery system especially for cancer therapy.