Metal-Organic Framework Accelerated One-Step Capture and Reduction of Palladium to Catalytically Active Nanoparticles.

Recovery of noble metals and in situ transforming to functional materials hold great promise in the sustainability of natural resources but remain as a challenge. Herein, the variable chemical microenvironments created by the inorganic-organic hybrid composition of metal-organic frameworks (MOFs) were exploited to tune the metal-support interactions, thus establishing an integrated strategy for recovering and reducing palladium (Pd). Assisted by sonic waves and alcoholic solvent, selective capture of Pd(II) from a complicated matrix to directly afford Pd nanoparticles (NPs) in MOFs can be achieved in one step within several minutes. Mechanism investigation reveals that the Pd binding site and the energy barriers between ionic and metallic status are sensitive to chemical environments in different frameworks. Thanks to the clean, dispersive, and uniform nature of Pd NPs, Pd@MOFs synthesized from a complicated environment exhibited high catalytic activity toward 4-nitrophenol reduction and Suzuki coupling reactions.

Tuning Proapoptotic Activity of a Phosphoric-Acid-Tethered Tetraphenylethene by Visible-Light-Triggered Isomerization and Switchable Protein Interactions for Cancer Therapy.

We herein report a phosphoric-acid-substituted tetraphenylethene (T-P) capable of adapting its geometric configuration and biological activity to the microenvironment upon light irradiation for apoptosis modulation. Different from most ultraviolet-responsive isomerization, T-P undergoes cis-trans isomerization under visible light irradiation, which is biocompatible and thus photo-modulation is possible in living biosystems. By using alkaline phosphatase (ALP) and albumin as dual targets, T-P isomers display different protein binding selectivity, cancer-cell internalization efficiency and apoptosis-inducing ability. The proapoptotic activity was found to be kinetically controlled by the enzymatic reaction with ALP and regulated by co-existing albumin. Motivated by these findings, two-way modulation of proapoptotic effect and on-demand boosting anticancer efficacy were realized in vitro and in vivo using light and endogenous proteins as multiple non-invasive switching stimuli.

Metal-Organic Framework-Based Nanoheater with Photo-Triggered Cascade Effects for On-Demand Suppression of Cellular Thermoresistance and Synergistic Cancer Therapy.

Nanomedicine with stable light-heat conversion and spatiotemporally controllable drug activation is crucial for the success of photothermal therapy (PTT). Herein, a metal-organic framework (MOF)-based nanoheater with light-triggered multi-responsiveness is engineered to in-situ and on-demand sensitize cancer cells to local hyperthermia. Well-dispersed platinum nanoparticles synthesized inside nanospaces of the MOF are employed as the near-infrared (NIR)-harvesting unit with stable and high light-heat conversion performance. A conformation switchable polymer shell is constructed as a secondary light-responding unit to gate the targeted activation of a molecular inhibitor against thermoresistance. By cascade transformation of light stimuli to downstream signals, the nanoheater enables inhibitor release to go with local heating at the same time restricted in lesion sites to maximize efficacy and minimize systemic toxicity. The efficient photothermal conversion and the blockage of cellular heat-protective pathways provide a dual-mode of action which selectively sensitizes cancer cells to hyperthermia in a spatiotemporally controlled manner. With NIR as the remote switch, the MOF-based nanosystem demonstrates localized and boosted PTT efficacy against cancer both in vitro and in vivo. These results present nanosized MOFs as tailorable and versatile platforms for synergistic and precise cancer therapy.

Photosensitizer with High Efficiency Generated in Cells via Light-Induced Self-Oligomerization of 4,6-Dibromothieno[3,4-b]thiophene Compound Entailing a Triphenyl Phosphonium Group.

Photodynamic therapy (PDT) has emerged as an attractive alternative in cancer therapy, but therapeutic effects suffer from low photosensitizing efficiency and poor retention of photosensitizes in cancer cells. This paper reports the photosensitizers which show absorption and emission in the long-wavelength region and high photosensitizing efficiency can be formed in situ in cells from 4,6-dibromothieno[3,4-b]thiophene derivative (TT-5-P) after white light irradiation. The self-oligomerization of TT-5-P is uptaken in cells upon light irradiation-induced cell apoptosis simultaneously and efficiently. In addition, the formation of oligomers (TT-5-Ps) enhances the retention time in cells remarkably, which is advantageous for boosting the photodynamic therapy efficiency. Moreover, the selectivity toward tumor cells of TT-5-P can be improved obviously via the formation of complex of TT-5-P with albumin. This in situ photoinduced self-oligomerization strategy can be utilized to design effective biomaterials for long-term imaging and improved therapy.

Engineering Peptide-Functionalized Biomimetic Nanointerfaces for Synergetic Capture of Circulating Tumor Cells in an EpCAM-Independent Manner.

Broad-spectrum detection and long-term monitoring of circulating tumor cells (CTCs) remain challenging due to the extreme rarity, heterogeneity, and dynamic nature of CTCs. Herein, a dual-affinity nanostructured platform was developed for capturing different subpopulations of CTCs and monitoring CTCs during treatment. Stepwise assembly of fibrous scaffolds, a ligand-exchangeable spacer, and a lysosomal protein transmembrane 4 ß (LAPTM4B)-targeting peptide creates biomimetic, stimuli-responsive, and multivalent-binding nanointerfaces, which enable harvest of CTCs directly from whole blood with high yield, purity, and viability. The stable overexpression of the target LAPTM4B protein in CTCs and the enhanced peptide-protein binding facilitate the capture of rare CTCs in patients at an early stage, detection of both epithelial-positive and nonepithelial CTCs, and tracking of therapeutic responses. The reversible release of CTCs allows downstream molecular analysis and identification of specific liver cancer genes. The consistency of the information with clinical diagnosis presents the prospect of this platform for early diagnosis, metastasis prediction, and prognosis assessment.

[Advances in the application of affinity separation for analyzing protein ubiquitination].

Protein ubiquitination is one of the most common yet complex post-translational modifications in eukaryotes that plays an important role in various biological processes including cell signal transduction, growth, and metabolism. Disorders in the ubiquitination process have been revealed to correlate with the occurrence and development of many diseases such as neurodegenerative disease, inflammation, and cancer. Investigation of protein ubiquitination is of great importance to uncover protein functions, understand the molecular mechanisms underlying biological processes, and develop novel strategies for disease treatment. Great advances have been made toward understanding protein ubiquitination; however, it remains a challenging task due to the high diversity of ubiquitination sites and structures, as well as the dynamic nature of ubiquitination in biological processes. Protein ubiquitination occurs through the formation of a covalent bond between the carboxyl terminus of ubiquitin and the ε-amino group of a lysine residue in the substrate. As a small protein, ubiquitin itself can be further modified by another ubiquitin molecule to form homotypic or heterotypic polyubiquitin chains. There are eight sites, namely seven lysine residues (K6, K11, K27, K29, K33, K48, and K63) and one N-terminal methionine (M1), in one ubiquitin molecule that can be used to form a ubiquitin dimer. The variations in modification sites, ubiquitin chain lengths, and conformations result in differences in protein sorting, cell signaling, and function. To resolve the high complexity of protein ubiquitination, new separation approaches are required. Affinity separation based on the specific recognition between biomolecules offers high selectivity and has been employed to study the structures and functions of ubiquitination. In addition, affinity ligands are central to the separation performance. Different affinity ligands have been developed and employed for the capture and enrichment of ubiquitylated proteins. Immunoaffinity separation based on antigen-antibody interactions has been one of the most classical separation methods. Antibodies against ubiquitin or different ubiquitin linkages have been developed and widely applied for the enrichment of ubiquitylated proteins or peptides. The specific capture allows the downstream identification of endogenous ubiquitination sites via mass spectrometry and thus facilitates understanding of the roles and dynamics of polyubiquitin signals. Ubiquitin-binding domains (UBDs) are a collection of modular protein domains that can interact with ubiquitin or polyubiquitin chains. Ubiquitin-associated domains, ubiquitin-interacting motifs, and ubiquitin-binding zinc finger domains are the most frequently used UBDs. Due to the moderate affinity of UBDs toward ubiquitin or ubiquitin chains, tandem ubiquitin-binding entities (TUBEs) have been engineered with high affinities (Kd in the nanomolar range) and exhibit potential as powerful tools for ubiquitination analysis. Because of their affinity and selectivity, UBDs and TUBEs have been applied for the isolation and identification of ubiquitylated targets in cancer cells and yeasts. Compared with antibodies and UBDs, peptides are smaller in size and can be facilely synthesized via chemical approaches. The modular structure of peptides allows for de novo design and screening of artificial ubiquitin affinity ligands for targeted capture of ubiquitinated proteins. Furthermore, the polyhistidine tag at the N-terminus of ubiquitin facilitates the purification of ubiquitylated substrates using immobilized metal affinity chromatography. Considering the high complexity of biosystems, strategies combining multiple affinity ligands have emerged to further improve separation efficiency and reduce background interference. Several combinations of antibodies with UBDs, antibodies with peptidyl tags, and UBDs with peptidyl tags have been developed and proven to be effective for the analysis of protein ubiquitination. These affinity-based approaches serve as important solutions for studying the structure-activity relationship of protein ubiquitination. This review highlights the applications and recent advances in affinity separation techniques for analyzing protein ubiquitination, focusing on the methods using antibodies, UBDs, peptides, and their combinations as affinity ligands. Further, their applications in the enrichment of ubiquitin-modified substrates and the identification of ubiquitination structures are introduced. Additionally, remaining challenges in affinity separation of protein ubiquitination and perspectives are discussed.

Metal-organic frameworks as advanced materials for sample preparation of bioactive peptides.

Development of novel affinity materials and separation techniques is crucial for the progress of modern proteomics and peptidomics. Detection of peptides and proteins from complex matrices still remains a challenging task due to the highly complicated biological composition, low abundance of target molecules, and large dynamic range of proteins. As an emerging area of analytical science, metal-organic framework (MOF)-based separation of proteins and peptides is attracting growing interest. This minireview summarizes the recent advances in MOF-based affinity materials for the sample preparation of proteins and peptides. Some newly emerging MOF nanoreactors for the degradation of peptides and proteins are introduced. An update of MOF-based affinity materials for the isolation of glycopeptides, phosphopeptides and low-abundance endogenous peptides in the last two years is focused on. The separation mechanism is discussed along with the chemical structures of MOFs. Finally, the remaining challenges and future development of MOFs in analyzing peptides and proteins in complicated biological samples are discussed.

Activity-Based Probe for Ratiometric Fluorescence Imaging of Caspase-3 in Living Cells.

Apoptosis plays an essential role in a multicellular organism's lifecycle. Developing technologies for selectively monitoring apoptotic processes can be useful not only in the evaluation of disease progression, but also in the assessment of their therapeutic intervention. However, quantitative imaging of cell apoptosis is still a challenge. In this work, we reported a cell-permeable peptide probe with a ratiometric fluorescence response specifically toward caspase-3, a key enzyme for the execution of apoptosis. This probe Ac-Tat-DEVD-CV consisted of a caspase-3 recognition sequence Asp-Glu-Val-Asp (DEVD), a cell-penetrating peptide Tat (RKKRRORRR), and a long wavelength fluorophore, cresyl violet (CV). Upon selective hydrolyzation by caspase-3, the probe released CV and displayed a ratiometric change in fluorescence. Facilitated by the cell-penetrating peptide, this probe can easily internalize into cells. The ratiometric response property bestowed the probe with advantages in the real-time quantification of caspase-3 activity, thus estimating the apoptotic stages in living cells. This method could offer opportunities to evaluate apoptosis-related disease progression and therapeutic monitoring.

Recent Advances in AIEgens for Metal Ion Biosensing and Bioimaging.

Metal ions play important roles in biological system. Approaches capable of selective and sensitive detection of metal ions in living biosystems provide in situ information and have attracted remarkable research attentions. Among these, fluorescence probes with aggregation-induced emission (AIE) behavior offer unique properties. A variety of AIE fluorogens (AIEgens) have been developed in the past decades for tracing metal ions. This review highlights recent advances (since 2015) in AIE-based sensors for detecting metal ions in biological systems. Major concerns will be devoted to the design principles, sensing performance, and bioimaging applications.