The performance of current multimodal imaging contrast agents is often constrained by the tunability of nanomaterial structural design. Herein, the influence of nanostructure on the overall imaging performance of a composite nanomaterial for multimodal imaging of brain tumors is studied. Newly designed near-infrared molecules (TC1) are encapsulated into nanocomposites with ultrasmall iron oxide nanoparticles (UIONPs), forming stable nanoagents for multimodal imaging and photothermal therapy (PTT). Through a modified nanoprecipitation method, the synthesis of nanocomposites denoted as HALF is realized, in which UIONPs are restricted to half of the nanosphere. Such a unique nanostructure that physically separates TC1 and UIONPs is found with capabilities of mitigating fluorescence quenching, preserving the good performance of photoacoustic imaging, and enhancing the magnetic resonance imaging signals. Decorated with a peptide ligand cRGD for better brain tumor targeting, HALF-cRGD is evaluated both in vitro and in vivo as imaging contrast agents and photothermal therapeutic agents. The good imaging performance and PTT effect of HALF-cRGD in mice models indicate that the rational design and control of nanostructures could optimize multimodal imaging performance using the same components.

Reactive oxygen species (ROS) are essential for the regulation of antitumor immune responses, where they could induce immunogenic cell death, promote antigen presentation, and activate immune cells. Here, we report the development of near-infrared (NIR)-driven immunostimulants, based on coupling upconversion nanoparticles with aggregation-induced emission luminogens (AIEgens), to integrate the immunological effects of ROS for enhanced adaptive antitumor immune responses. Intratumorally injected AIEgen-upconversion nanoparticles produce high-dose ROS under high-power NIR irradiation, which induces immunogenic cell death and antigen release. These nanoparticles can also capture the released antigens and deliver them to lymph nodes. Upon subsequent low-power NIR treatment of lymph nodes, low-dose ROS are generated to further trigger efficient T cell immune responses through activation of dendritic cells, preventing both local tumor recurrence and distant tumor growth. The utility of dual-mode pumping power on AIEgen-coupled upconversion nanoparticles offers a powerful and controllable platform to activate adaptive immune systems for tumor immunotherapy.

In article number 2001338, Bin Liu and co-workers report a material platform that exploits bacteria as a template to synthesize polymers with aggregation-induced emission characteristics. The bacterium-templated polymer shows very weak fluorescence in aqueous media and the fluorescence is turned on upon recognition of the templated bacteria. The incorporated aggregation-induced emission fluorogens can act as an efficient photosensitizer, which endows the templated polymers with the ability to selectively kill bacteria.

The recognition and inactivation of specific pathogenic bacteria remain an enormous scientific challenge and an important therapeutic goal. Therefore, materials that can selectively target and kill specific pathogenic bacteria, without harming beneficial strains are highly desirable. Here, a material platform is reported that exploits bacteria as a template to synthesize polymers with aggregation-induced emission (AIE) characteristic by copper-catalyzed atom transfer radical polymerization for self-selective killing of the bacteria that templates them with no antimicrobial resistance. The bacteria-templated polymers show very weak fluorescence in aqueous media, however, the fluorescence is turned on upon recognition of the bacteria used as the template to synthesize the polymer even at a low concentration of 600 ng mL(-1). Moreover, the incorporated AIE fluorogens (AIEgens) can act as an efficient photosensitizer for reactive oxygen species (ROS) generation after bacteria surface binding, which endows the templated polymers with the capability for selective bacterial killing. The bacterium-templated synthesis is generally applicable to a wide range of bacteria, including clinically isolated multidrug-resistant bacterial strains. It is envisioned that the bacterium-templated method provides a new strategy for bacteria-specific diagnostic and therapeutic applications.

Polymeric nanoparticles play important roles in the delivery of a multitude of therapeutic and imaging contrast agents. Although these nanomaterials have shown tremendous potential in disease diagnosis and therapy, there have been many reports on the failure of these nanoparticles in realizing their intended objectives due to an individual or a combination of factors, which have collectively challenged the merit of nanomedicine for disease theranostics. Herein, we investigate the interactions of polymeric nanoparticles with biological entities from molecular to organism levels. Specifically, the protein corona formation, in vitro endothelial uptake, and in vivo circulation time of these nanoparticles are systematically probed. We identify the crucial role of nano carrier lipophilicity, zeta-potential, and size in controlling the interactions between nanoparticles and biological systems and propose a two-step framework in formulating a single nanoparticle system to regulate multiple biological effects. This study provides insight into the rational design and optimization of the performance of polymeric nanoparticles to advance their theranostic and nanomedicine applications.

Reactivity-based organic bioprobes have been increasingly designed and developed in the last couple of years to address important questions in numerous fields, particularly in biology and medicine. Contrary to the conventional lock-and-key bioprobes, which rely on molecular recognition to probe biological systems and impart sensing specificity, reactivity-based bioprobes capitalize on molecular reactivity for selective target detection. In fact, reactivity-based sensing exploits the intrinsic differences in chemical reactivity to differentiate various chemical species possessing similar size and shape in biological systems. This unique sensing mechanism has been effective for the detection of a wide range of chemical analytes in living cells, tissues, and animals, although bioprobes with additional functionalities are increasingly required in the quest to unravel and understand the complex biological systems. This is why the integration of diagnostic and therapeutic functions in one theranostic platform has become a continuous pursuit in the development of bioprobes in recent years. To this end, numerous design and synthetic approaches have been explored, notably that combining different organic materials with distinct functionalities into one integrated system, also known as "all-in-one" strategy. Nevertheless, the "all-in-one" strategy is prone to design complexity and unsatisfactory reproducibility. To minimize these undesirable hurdles, the deliberate design and engineering of simple organic molecules with multiple functionalities have been actively pursued, leading to the emergence of a unique approach known as "one-for-all" strategy. A prominent example of this approach leverages on fluorogens with aggregation-induced emission (AIE) characteristic. Through smart molecular engineering, we and other groups have recently shown that conventional organic AIE fluorogens can be specifically tailored to offer both imaging and therapeutic functionalities, such as photosensitizing ability to facilitate photodynamic therapy. The creation of this new class of versatile organic theranostic bioprobes with simultaneous imaging and therapeutic capabilities has further enabled image-guided chemotherapy and image-guided photodynamic therapy. Essentially, from this endeavor, replacing the fluorophores of conventional reactivity-based bioprobes with multifunctional molecules will yield reactivity-based organic theranostic bioprobes with enhanced capabilities and improved performance. In this Account, we summarize the latest advancement of reactivity-based theranostic bioprobes. To start with, we discuss the fundamental differences between conventional lock-and-key and reactivity-based sensing mechanisms, followed by general design routes of reactivity-based organic theranostic bioprobes. We then describe our efforts in recent years in formulating reactivity-based organic biosensing/imaging probes and multifunctional theranostic probes as well as in utilizing these bioprobes in detecting various chemical species in living systems, such as free radicals and toxins, and in diagnosing and treating cancer and bacterial infections. Finally, we highlight current challenges and opportunities in the conclusions and outlook section. With this Account, we seek to further stimulate research activities and closer collaborations among the research fields of chemistry, materials, and biology to push the boundary of this emerging field and promote reactivity-based theranostics for practical applications and clinical translations.

Photosensitizer (PS) serves as the central element of photodynamic therapy (PDT). The use of common nanoparticles (NPs) for PDT has typically been rendered less effective by the undesirable aggregation-caused quenching (ACQ) effect, resulting in quenched fluorescence and reduced reactive oxygen species (ROS) generation that diminish the imaging quality and PDT efficacy. To overcome the ACQ effect and to enhance the overall efficacy of PDT, herein, integrin ανβ3-targeted organic nanodots for image-guided PDT were designed and synthesized based on a red emissive aggregation-induced emission (AIE) PS. Methods: The TPETS nanodots were prepared by nano-precipitation method and further conjugated with thiolated cRGD (cRGD-SH) through a click reaction to yield the targeted TPETS nanodots (T-TPETS nanodots). Nanodots were characterized for encapsulation efficiency, conjugation rate, particle size, absorption and emission spectra and ROS production. The targeted fluorescence imaging and antitumor efficacy of T-TPETS nanodot were evaluated both in vitro and in vivo. The mechanism of cell apoptosis induced by T-TPETS nanodot mediated-PDT was explored. The biocompatibility and toxicity of the nanodots was examined using cytotoxicity test, hemolysis assay, blood biochemistry test and histological staining. Results: The obtained nanodots show bright red fluorescence and highly effective 1O2 generation in aggregate state. Both in vitro and in vivo experiments demonstrate that the nanodots exhibit excellent tumor-targeted imaging performance, which facilitates image-guided PDT for tumor ablation in a hepatocellular carcinoma model. Detailed analysis reveals that the nanodot-mediated PDT is able to induce time- and concentration-dependent cell death. The use of PDT at a high PDT intensity leads to direct cell necrosis, while cell apoptosis via the mitochondria-mediated pathway is achieved under low PDT intensity. Conclusion: Our results suggest that well-designed AIE nanodots are promising for image-guided PDT applications.

The detection and elimination of intracellular bacteria remain a major challenge. In this work, we report an aggregation-induced emission (AIE) bioprobe that can detect bacterial infection and kill bacteria surviving inside macrophages through a dynamic process, notably specific molecular tailoring of the probe by caspase-1 activation in infected macrophages and accumulation of the residue on phagosomes containing bacteria, leading to light-up fluorescent signals. Moreover, the AIEgen can serve as a photosensitizer for generation of reactive oxygen species (ROS); and the average ROS indicator fluorescent signal intensity per unit area in the bacterial phagosomes is approximately 2.7-fold higher than that in the cytoplasm. This, in turn, induces bacteria killing with high efficiency and minimal cytotoxicity towards macrophages. We envision that this specific light-up bioprobe may provide a new approach for selective and sensitive detection and eradication of intracellular bacterial infections.

Horseradish peroxidase (HRP) and fluorogen-dextran conjugate are tracers extensively used for injection-based lineage tracing. However, HRP is sensitive to proteolytic digestion, whereas the high-molecular-weight dextran may have antigenicity. Small molecular tracers can overcome these problems, but they usually diffuse from labeled cells, causing inaccurate information. Herein, we developed a small-molecular-weight fluorogen with aggregation-induced emission (AIEgen) for embryonic cell tracing with strong signals against tracer dilution caused by cell division. Once injected into the ancestor cells, the AIEgen can be entrapped in the cells without leakage because of the two hydrophilic and neutral arms. Consequently, it can specifically trace the progenies of the treated ancestor cells. More importantly, the operating concentration of AIEgen can be much higher than that of fluorogens with aggregation-caused quenching, which provides bright signals in daughter cells during embryonic cell tracing, thus overcoming the problem of fast signal degradation typically encountered with the use of traditional cell tracers.

The near-infrared window between 1000 and 1700 nm, commonly termed the "second near-infrared (NIR-II) window," has quickly emerged as a highly attractive optical region for biological imaging. In contrast to conventional imaging in the visible region between 400 and 700 nm, as well as in the first NIR (NIR-I) window between 700 and 900 nm, NIR-II biological imaging offers numerous merits, including higher spatial resolution, deeper penetration depth, and lower optical absorption and scattering from biological substrates with minimal tissue autofluorescence. Noninvasive imaging techniques, specifically NIR-II fluorescence and photoacoustic (PA) imaging, have embodied the attractiveness of NIR-II optical imaging, with several NIR-II contrast agents demonstrating superior performance to the clinically approved NIR-I agents. Consequently, NIR-II biological imaging has been increasingly explored due to its tremendous potential for preclinical studies and clinical utility. Herein, the progress of optical imaging in the NIR-II window is reported. Starting with highlighting the importance of biological imaging in the NIR-II spectral region, the emergence and latest development of various NIR-II fluorescence and PA imaging probes and their applications are then discussed. Perspectives on the promises and challenges facing this nascent yet exciting field are then given.

AbstractBio‐orthogonal tumor labeling is more effective in delivering imaging agents or drugs to a tumor site than active targeting strategy owing to covalent ligation. However, to date, tumor‐specific imaging through bio‐orthogonal labeling largely relies on body clearance to differentiate target from the intrinsic probe signal owing to the lack of light‐up probes for in vivo bio‐orthogonal labeling. Now the first light‐up probe based on a fluorogen with aggregation‐induced emission for in vivo bio‐orthogonal fluorescence turn‐on tumor labeling is presented. The probe has low background fluorescence in aqueous media, showing negligible non‐specific interaction with normal tissues. Once it reacts with azide groups introduced to tumor cells through metabolic engineering, the probe fluorescence is lightened up very quickly, enabling rapid tumor‐specific imaging. The photosensitizing ability was also used to realize effective image‐guided photodynamic tumor therapy.

Bacterial infection is one of the most serious physiological conditions threatening human health. There is an increasing demand for more effective bacterial diagnosis and treatment through noninvasive theranostic approaches. Herein, a new strategy is reported to achieve in vivo metabolic labeling of bacteria through the use of MIL-100 (Fe) nanoparticles (NPs) as the nanocarrier for precise delivery of 3-azido-D-alanine (D-AzAla). After intravenous injection, MIL-100 (Fe) NPs can accumulate preferentially and degrade rapidly within the high H2O2 inflammatory environment, releasing D-AzAla in the process. D-AzAla is selectively integrated into the cell walls of bacteria, which is confirmed by fluorescence signals from clickable DBCO-Cy5. Ultrasmall photosensitizer NPs with aggregation-induced emission characteristics are subsequently designed to react with the modified bacteria through in vivo click chemistry. Through photodynamic therapy, the amount of bacteria on the infected tissue can be significantly reduced. Overall, this study demonstrates the advantages of metal-organic-framework-assisted bacteria metabolic labeling strategy for precise bacterial detection and therapy guided by fluorescence imaging.

The growing importance of biodegradable conducting polymers (CPs) have fueled the rapid development of this unique class of polymeric materials in recent years. Possessing both the electrical conductivity approaching those of metallic conductors and the biodegradability of biocompatible polymers, biodegradable CPs are highly sought after. In fact, they have emerged as the ideal biomaterials, having immense potential for augmenting a wide range of practical biomedical applications. Herein, we provide a broad overview of recent advances in the development of biodegradable CPs and their biomedical applications. We first introduce the fundamentals of conducting and biodegradable polymers, followed by discussions on the major strategies currently used to fabricate biodegradable CPs. We then highlight the potential biomedical applications of biodegradable CPs (specifically those for tissue engineering, regenerative medicine, and biomedical imaging as well as biomedical implants, bioelectronics devices, and consumer electronics). We conclude this review by offering our perspectives on the current challenges and future opportunities facing the development and practical applications of biodegradable CPs.

Extracellular vesicles (EVs) play an important role as active messengers in intercellular communication and distant microenvironment modeling. Increasingly, these EVs are recognized as important biomarkers for clinical diagnostics. However, current isolation methods of EVs are time-consuming and ineffective due to the high diffusive characteristics of nanoparticles coupled with fluid flow instability. Here, we develop a microfluidic CEntrifugal Nanoparticles Separation and Extraction (µCENSE) platform for the rapid and label-free isolation of microvesicles. By utilizing centrifugal microhydrodynamics, we subject the nanosuspensions between 100 nm and 1000 nm to a unique fluid flow resulting in a zonal separation into different outlets for easy post-processing. Our centrifugal platform utilizes a gentle and efficient size-based separation without the requirements of syringe pump and other accessories. Based on our results, we report a high separation efficiency of 90% and an extraction purity of 85% within a single platform. Importantly, we demonstrate high EV extraction using a table top centrifuge within a short duration of eight minutes. The simple processes and the small volume requirement further enhance the utility of the platform. With this platform, it serves as a potential for liquid biopsy extraction and point-of-care diagnostics.

Aptamer-based biosensing, which uses short, single-stranded nucleic acid segments to bind to a target, can be advantageous over antibody-based diagnostics due to the ease of synthesis and high stability of aptamers. However, the development of most aptamer-based sensors (aptasensors) is still in its initial stages and many factors affecting their performance have not been studied in great detail. Here, we enhance the sensing specificity of a fluorescence resonance energy transfer (FRET)-based MoS2 nanosheet aptasensor in detecting the malarial biomarker Plasmodium lactate dehydrogenase (pLDH). In this sensing scheme, the presence of target is signaled by an increase in fluorescence when fluorescently-labeled aptamers bind to pLDH and release from a quenching material. Interestingly, unlike most of the reported literature on aptasensors, we observe that non-target proteins also cause a considerable increase in the detected fluorescence. This may be due to the nonspecific adsorption of proteins onto the fluorescence quencher, leading to the displacement of aptamers from the quencher surface. To reduce this nonspecific association and to enhance the sensor specificity, we propose the application of a surface blocking agent to the quenching material. Importantly, we demonstrate that the sensing specificity of the MoS2 nanosheet-based aptasensor towards target pLDH biomolecules can be significantly enhanced through surface passivation, thus contributing to the development of highly selective and robust point-of-care malaria diagnostics.

Nanofibers have emerged as exciting one-dimensional nanomaterials for a broad spectrum of research and commercial applications owing to their unique physicochemical properties and characteristics. As a class of nanomaterials with cross-sectional diameters ranging from tens to hundreds of nanometers, nanofibers possess extremely high specific surface area and surface area-to-volume ratio. They are capable of forming networks of highly porous mesh with remarkable interconnectivity between their pores, making them an attractive choice for a host of advanced applications. In fact, the significant impact of nanofiber technology can be traced from the wide range of fundamental materials that can be used for the synthesis of nanofibers. These include natural polymers, synthetic polymers, carbon-based materials, semiconducting materials, and composite materials. Correspondingly, the emerging proof-of-concept applications of nanofibers spanning several important areas have been rapidly reported. This Review explores the current status and up-and-coming development of nanofiber technology, with an emphasis on its syntheses and applications. First, we highlight the current and emerging strategies used in synthesizing nanofibers. We briefly introduce the various established nanofiber synthesis techniques, especially the electrospinning method. We then focus on the emerging nanofiber synthesis strategies, such as solution blow spinning, centrifugal jet spinning, and electrohydrodynamic direct writing. Next, we discuss the emerging applications of nanofiber technology in various fields, specifically in three important areas of energy generation and storage, water treatment and environmental remediation, and healthcare and biomedical engineering. Despite all these advancements, there are still challenges to be addressed and overcome for nanofiber technology to move towards maturation. Nevertheless, we envision that with further progress in the development of nanofiber synthesis strategies and identification of “killer” applications of nanofibers, nanofiber technology will mature and move beyond its current state towards commercial realization and applications.

NIR II conjugated polymer nanoparticles with good biocompatibility, excellent photoacoustic stability and high imaging contrast are formulated, which allows highly efficient imaging of orthotopic brain tumors with a high signal/background ratio and a good penetration depth.

A novel graphene oxide (GO) nanosuspension liquid-based microfluidic tactile sensor is developed. It comprises a UV ozone-bonded Ecoflex-polydimethylsiloxane microfluidic assembly filled with GO nanosuspension, which serves as the working fluid of the tactile sensor. This device is highly flexible and able to withstand numerous modes of deformation as well as distinguish various user-applied mechanical forces it is subjected to, including pressing, stretching, and bending. This tactile sensor is also highly deformable and wearable, and capable of recognizing and differentiating distinct hand muscle-induced motions, such as finger flexing and fist clenching. Moreover, subtle differences in the handgrip strength derived from the first clenching gesture can be identified based on the electrical response of our device. This work highlights the potential application of the GO nanosuspension liquid-based flexible microfluidic tactile sensing platform as a wearable diagnostic and prognostic device for real-time health monitoring. Also importantly, this work can further facilitate the exploration and potential realization of a functional liquid-state device technology with superior mechanical flexibility and conformability.

Cancer is currently one of the top non-communicable human diseases, and continual research and developmental efforts are being made to better understand and manage this disease. More recently, with the improved understanding in cancer biology as well as the advancements made in microtechnology and rapid prototyping, microfluidics is increasingly being explored and even validated for use in the detection, diagnosis and treatment of cancer. With inherent advantages such as small sample volume, high sensitivity and fast processing time, microfluidics is well-positioned to serve as a promising platform for applications in oncology. In this review, we look at the recent advances in the use of microfluidics, from basic research such as understanding cancer cell phenotypes as well as metastatic behaviors to applications such as the detection, diagnosis, prognosis and drug screening. We then conclude with a future outlook on this promising technology.

The novel application of two-dimensional (2D) single-layer ternary chalcogenide nanosheets as "capture-release" fluorescence-based biomolecular nanosensors is demonstrated. Fluorescently labeled biomolecular probe is first captured by the ultrathin Ta2 NiS5 nanosheets and then released upon adding analyte containing a target biomolecule due to the higher probe-target affinity. Here, the authors use a nucleic acid probe for the model target biomolecule Plasmodium lactate dehydrogenase, which is an important malarial biomarker. The ultrathin Ta2 NiS5 nanosheet serves as a highly efficient fluorescence quencher and the nanosensor developed from the nanosheet is highly sensitive and specific toward the target biomolecule. Apart from the specificity toward the target biomolecule in homogeneous solutions, the developed nanosensor is capable of detecting and differentiating the target in heterogeneous solutions consisting of either a mixture of biomolecules or serum, with exceptional specificity. The simplicity of the "capture-release" method, by eliminating the need for preincubation of the probe with the test sample, may facilitate further development of portable and rapid biosensors. The authors anticipate that this ternary chalcogenide nanosheet-based biomolecular nanosensor will be useful for the rapid detection and differentiation of a wide range of chemical and biological species.