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Cyclic peptides have attracted tremendous attention in the pharmaceutical industry owing to their excellent cell penetrability, stability, thermostability, and drug-like properties. However, the currently available facile methodologies for creating such peptides are rather limited. Herein, we reported an efficient and direct peptide cyclization via rhodium(III)-catalyzed C(7)-H maleimidation. Notably, this catalytical system has excellent regioselectivity and high tolerance of functional groups which enable late-stage cyclization of peptides. This new architecture of cyclic peptides exhibits higher bioactivity than its parent linear peptides. Moreover, the Trp-substituted maleimide displays excellent reactivity towards Michael addition, indicating its potential as new click functional group for applications in chemical biology and medicinal chemistry.

Surface-enhanced Raman spectroscopy (SERS) nanotags hold a unique place among bioimaging contrast agents due to their fingerprint-like spectra, which provide one of the highest degrees of detection specificity. However, in order to achieve a sufficiently high signal intensity, targeting capabilities, and biocompatibility, all components of nanotags must be rationally designed and tailored to a specific application. Design parameters include fine-tuning the properties of the plasmonic core as well as optimizing the choice of Raman reporter molecule, surface coating, and targeting moieties for the intended application. This review introduces readers to the principles of SERS nanotag design and discusses both established and emerging protocols of their synthesis, with a specific focus on the construction of SERS nanotags in the context of bioimaging and theranostics.

Phospholipid nanocarriers have been widely explored for theranostic and nanomedicine applications. These amphiphilic nanocarriers possess outstanding cargo encapsulation efficiency, high water dispersibility, and excellent biocompatibility, which render them promising for drug delivery and bioimaging applications. While the biological applications of phospholipid nanocarriers have been well documented, the fundamental aspects of the phospholipid-cell interactions beyond cytotoxicity have been less investigated. In particular, the effect of phospholipid nanocarriers on collective cell behaviors has not been elucidated. Herein, we evaluate the interactions of phospholipid nanocarriers possessing different functional groups and sizes with normal and cancerous immortalized breast epithelial cell sheets with varying metastatic potential. Specifically, we examine the impact of nanocarrier treatments on the collective migratory dynamics of these cell sheets. We observe that phospholipid nanocarriers induce differential collective cell migratory behaviors, where the migration speed of normal and cancerous breast epithelial cell sheets is retarded and accelerated, respectively. To a certain extent, the nanocarriers are able to alter the migration trajectory of the cancerous breast epithelial cells. Furthermore, phospholipid nanocarriers could modulate the stiffness of the nuclei, cytoplasm, and cell-cell junctions of the breast epithelial cell sheets, remodel their actin filament arrangement, and regulate the expressions of the actin-related proteins. We anticipate that this work will further shed light on nanomaterial-cell interactions and provide guidelines for rational and safer designs and applications of phospholipid nanocarriers for cancer theranostics and nanomedicine.

Phospholipid nanoparticles have been actively employed for numerous biomedical applications. A key factor in ensuring effective and safe applications of these nanomaterials is the regulation of their interactions with target cells, which is significantly dependent on an in-depth understanding of the nanoparticle-cell interactions. To date, most studies investigating these nano-bio interactions have been performed under static conditions and may lack crucial real-time information. It is, however, noteworthy that the nanoparticle-cell interactions are highly dynamic. Consequently, to gain a deeper insight into the cellular effects of phospholipid nanoparticles, real-time observation of cellular dynamics after nanoparticle introduction is necessary. Herein, a proof-of-concept in situ visualization of the dynamic cellular effects of sub-100 nm phospholipid nanoparticles using high-speed scanning ion conductance microscopy (HS-SICM) is reported. It is revealed that upon introduction into the cellular environment, within a short timescale of hundreds of seconds, phospholipid nanoparticles can selectively modulate the edge motility and surface roughness of healthy fibroblast and cancerous epithelial cells. Furthermore, the dynamic deformation profiles of these cells can be selectively altered in the presence of phospholipid nanoparticles. This work is anticipated to further shed light on the real-time nanoparticle-cell interactions for improved formulation of phospholipid nanoparticles for numerous bioapplications.

A novel mitochondria-targeting molecular rotator FD was designed to visualize changes in viscosity under hypoxic conditions in vitro and in vivo. Importantly, FD can be used to detect changes in the blood viscosity of liver cancer and liver cirrhosis patients, and also rehabilitation of liver disease.

Kenry was a research fellow at the National University of Singapore (NUS), where he obtained his PhD. His research focuses on functional nanomaterials for theranostics and nanomedicine. He is currently a research fellow at the Dana-Farber Cancer Institute and Harvard Medical School. Ben Zhong Tang received his BS and PhD degrees from South China University of Technology and Kyoto University, respectively. He conducted postdoctoral study at the University of Toronto. He joined the Hong Kong University of Science and Technology in 1994 and was promoted to chair professor in 2008. His research interests include macromolecular chemistry, materials science, and theranostics. Bin Liu is currently the Provost’s Chair Professor and head of the NUS Department of Chemical and Biomolecular Engineering. She received her PhD from the same institution and did her postdoctoral work at the University of California, Santa Barbara. Her research focuses on organic functional nanomaterials for energy and biomedical applications.

Traditional photosensitizers (PSs) show reduced singlet oxygen (1 O2 ) production and quenched fluorescence upon aggregation in aqueous media, which greatly affect their efficiency in photodynamic therapy (PDT). Meanwhile, non-targeting PSs generally yield low efficiency in antibacterial performance due to their short lifetimes and small effective working radii. Herein, a water-dispersible membrane anchor (TBD-anchor) PS with aggregation-induced emission is designed and synthesized to generate 1 O2 on the bacterial membrane. TBD-anchor showed efficient antibacterial performance towards both Gram-negative (Escherichia coli) and Gram-positive bacteria (Staphylococcus aureus). Over 99.8 % killing efficiency was obtained for methicillin-resistant S. aureus (MRSA) when they were exposed to 0.8 μm of TBD-anchor at a low white light dose (25 mW cm-2 ) for 10 minutes. TBD-anchor thus shows great promise as an effective antimicrobial agent to combat the menace of multidrug-resistant bacteria.

A bacterial metabolic probe combining D-alanine and a photosensitizer with aggregation-induced emission (AIE) has been developed for in vivo light-up imaging of bacterial walls and efficient antibacterial therapy. This activatable probe could serve as a promising non-antibiotic tool for diagnosis and treatment of biofilms and intracellular bacteria, as well as multi-resistant bacterial infections.

The rapid advancement of bio-orthogonal click chemistry in the past decade has enabled the study and precise manipulation of biological processes within living organisms. The capability to induce fast and selective chemical reactions between two exogenous complementary moieties in living systems, with negligible perturbation to their native activities, have rendered bio-orthogonal click chemistry highly promising for a multitude of bioapplications. This review provides an overview of recent developments in bio-orthogonal click chemistry for bioimaging in living organisms. Bio-orthogonal click reactions commonly performed in in vivo systems and their in vivo biological labeling and imaging applications, particularly for the visualization of biomolecular processes, therapeutic cells, tumors, and bacteria, are discussed. Potential future directions of this exciting area are also presented.

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.

In the last two decades, the application of surface enhanced Raman scattering (SERS) nanoparticles for preclinical cancer imaging has attracted increasing attention. Raman imaging with SERS nanoparticles offers unparalleled sensitivity, providing a platform for molecular targeting, and granting multiplexed and multimodal imaging capabilities. Recent progress has been facilitated not only by the optimization of the SERS contrast agents themselves, but also by the developments in Raman imaging approaches and instrumentation. In this article, we review the principles of Raman scattering and SERS, present advances in Raman instrumentation specific to cancer imaging, and discuss the biological means of ensuring selective in vivo uptake of SERS contrast agents for targeted, multiplexed, and multimodal imaging applications. We offer our perspective on areas that must be addressed in order to facilitate the clinical translation of SERS contrast agents for in vivo imaging in oncology.

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.

Protected by the host cells, the hidden intracellular bacteria are typically difficult to kill by common antibiotics and cannot be visualized without complex cellular pretreatments. Herein, we successfully developed a bacteria-metabolizable dual-functional probe TPEPy-d-Ala, which is based on d-alanine and a photosensitizer with aggregation-induced emission for fluorescence turn-on imaging of intracellular bacteria in living host cells and photodynamic ablation in situ. Once metabolically incorporated into bacterial peptidoglycan, the intramolecular motions of TPEPy-d-Ala are inhibited, leading to an enhanced fluorescent signal, which allows the clear visualization of the intracellular bacteria. Moreover, TPEPy-d-Ala can effectively ablate the labeled intracellular bacteria in situ owing to covalent ligation to peptidoglycan, yielding a low intracellular minimum inhibitory concentration (MIC) of 20±0.5 μg mL-1 , much more efficient than that of a commonly used antibiotic, vancomycin.

o-Alkenylation of unprotected phenols has been developed by direct C-H functionalization catalyzed by PdII . This work features phenol group as a directing group and realizes highly site-selective C-H bond functionalization of phenols to achieve the corresponding products in moderate to excellent yields at 60 °C. The advantages of this reaction include unprecedented C-H functionalization using phenol as a directing group, high regioselectivity, good substrate scope, mild reaction conditions, and high efficiency. To the best of our knowledge, this is the first example of a regioselective C-H alkenylation of unprotected phenols utilizing phenolic hydroxyl group as a directing group. The alkenylation of unprotected tyrosine and intramolecular cyclization are also successfully carried out under this catalytic system in good yields. Furthermore, this novel method enables a late-stage modification of complex phenol-containing bioactive molecules toward a diversity-oriented drug discovery.