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Schiff base, an important family of reaction in click chemistry, has received significant attention in the formation of self-healing hydrogels in recent years. Schiff base reversibly reacts even in mild conditions, which allows hydrogels with self-healing ability to recover their structures and functions after damages. Moreover, pH-sensitivity of the Schiff base offers the hydrogels response to biologically relevant stimuli. Different types of Schiff base can provide the hydrogels with tunable mechanical properties and chemical stabilities. In this review, we summarized the design and preparation of hydrogels based on various types of Schiff base linkages, as well as the biomedical applications of hydrogels in drug delivery, tissue regeneration, wound healing, tissue adhesives, bioprinting, and biosensors.

In 2022, the Nobel Prize in Chemistry was awarded to Bertozzi, Meldal, and Sharpless “for the development of click chemistry and biorthogonal chemistry”. Since 2001, when the concept of click chemistry was advanced by Sharpless laboratory, synthetic chemists started to envision click reactions as the preferred choice of synthetic methodology employed to create new functions. This brief perspective will summarize research performed in our laboratories with the classic Cu(I)-catalyzed azide-alkyne click (CuAAC) reaction elaborated by Meldal and Sharpless, with the thio-bromo click (TBC) and with the less-used, irreversible TERminator Multifunctional INItiator (TERMINI) dual click (TBC) reactions, the last two elaborated in our laboratory. These click reactions will be used to assemble, by accelerated modular-orthogonal methodologies, complex macromolecules and self-organizations of biological relevance. Self-assembling amphiphilic Janus dendrimers and Janus glycodendrimers together with their biological membrane mimics known as dendrimersomes and glycodendrimersomes as well as simple methodologies to assemble macromolecules with perfect and complex architecture such as dendrimers from commercial monomers and building blocks will be discussed. This perspective is dedicated to the 75th anniversary of Professor Bogdan C. Simionescu, the son of my (VP) Ph.D. mentor, Professor Cristofor I. Simionescu, who as his father, took both science and science administration in his hands, and dedicated his life to handling them in a tandem way, to their best.

Click chemistry is a concept in which modular synthesis is used to rapidly find new molecules with desirable properties 1 . Copper( i )-catalysed azide–alkyne cycloaddition (CuAAC) triazole annulation and sulfur( vi ) fluoride exchange (SuFEx) catalysis are widely regarded as click reactions 2 – 4 , providing rapid access to their products in yields approaching 100% while being largely orthogonal to other reactions. However, in the case of CuAAC reactions, the availability of azide reagents is limited owing to their potential toxicity and the risk of explosion involved in their preparation. Here we report another reaction to add to the click reaction family: the formation of azides from primary amines, one of the most abundant functional groups 5 . The reaction uses just one equivalent of a simple diazotizing species, fluorosulfuryl azide 6 – 11 (FSO 2 N 3 ), and enables the preparation of over 1,200 azides on 96-well plates in a safe and practical manner. This reliable transformation is a powerful tool for the CuAAC triazole annulation, the most widely used click reaction at present. This method greatly expands the number of accessible azides and 1,2,3-triazoles and, given the ubiquity of the CuAAC reaction, it should find application in organic synthesis, medicinal chemistry, chemical biology and materials science. A ‘click’ reaction is developed for the simple and rapid formation of azides from primary amines, and is used to prepare a library of over 1,200 azides for subsequent use in the existing triazole annulation click reaction.

Targeted immunomodulation of dendritic cells (DCs) in vivo will enable manipulation of T-cell priming and amplification of anticancer immune responses, but a general strategy has been lacking. Here we show that DCs concentrated by a biomaterial can be metabolically labelled with azido groups in situ, which allows for their subsequent tracking and targeted modulation over time. Azido-labelled DCs were detected in lymph nodes for weeks, and could covalently capture dibenzocyclooctyne (DBCO)-bearing antigens and adjuvants via efficient Click chemistry for improved antigen-specific CD8 + T-cell responses and antitumour efficacy. We also show that azido labelling of DCs allowed for in vitro and in vivo conjugation of DBCO-modified cytokines, including DBCO–IL-15/IL-15Rα, to improve priming of antigen-specific CD8 + T cells. This DC labelling and targeted modulation technology provides an unprecedented strategy for manipulating DCs and regulating DC–T-cell interactions in vivo. Dendritic cells concentrated in vivo within a hydrogel have been metabolically tagged with azido groups to enable tracking as well as delivery of antigens, adjuvants and cytokines, thereby facilitating targeted immunomodulation.

Defining protein–protein interactions (PPIs) in their native environment is crucial to understanding protein structure and function. Cross-linking–mass spectrometry (XL-MS) has proven effective in capturing PPIs in living cells; however, the proteome coverage remains limited. Here, we have developed a robust in vivo XL-MS platformto facilitate in-depth PPI mapping by integrating a multifunctional MS-cleavable cross-linker with sample preparation strategies and high-resolution MS. The advancement of click chemistry–based enrichment significantly enhanced the detection of cross-linked peptides for proteome-wide analyses. This platform enabled the identification of 13,904 unique lysine–lysine linkages from in vivo cross-linked HEK 293 cells, permitting construction of the largest in vivo PPI network to date, comprising 6,439 interactions among 2,484 proteins. These results allowed us to generate a highly detailed yet panoramic portrait of human interactomes associated with diverse cellular pathways. The strategy presented here signifies a technological advancement for in vivo PPI mapping at the systems level and can be generalized for charting protein interaction landscapes in any organisms.

Alkyne‐based click polymerizations have been nurtured into a powerful synthetic technique for the preparation of new polymers with advanced structures and versatile properties. Among them, the emerging thiol‐yne, hydroxyl‐yne, and amino‐yne click polymerizations have made remarkable progress from reactions to applications. These polymerizations avoid the usage of inherently dangerous monomers and are safer to operate than the classical azide‐alkyne click polymerization (AACP), making them more prospective for diverse applications. To greatly promote the new alkyne‐based click polymerizations beyond AACP, a new concept of “X‐yne click polymerization” is proposed to unify them, where “X” denotes the monomers that can react with alkynes under mild reaction conditions, including thiols, alcohols, amines, and other promising ones. In this review, we mainly present a brief account of the progress of X‐yne click polymerization and discuss in detail the challenges and opportunities in this field.

Controlled activation is a critical component in prodrug development. Here we report a concentration-sensitive platform approach for bioorthogonal prodrug activation by taking advantage of reaction kinetics. Using two ‘click and release’ systems, we demonstrate enrichment and prodrug activation specifically in mitochondria to demonstrate the principle of the approach. In both cases, the payload (doxorubicin or carbon monoxide) was released inside the mitochondrial matrix following the enrichment-initiated click reaction. Furthermore, mitochondria-targeted delivery yielded substantial augmentation of functional biological and therapeutic effects in vitro and in vivo when compared to controls, which did not result in enrichment. This method is thus a platform for targeted drug delivery that is amenable to conjugation with a variety of molecules and is not limited to cell-surface delivery. Taken together, these two 'click and release' pairs clearly demonstrate the concept of enrichment-triggered drug release and the critical feasibility of treating clinically relevant diseases such as acute liver injury and cancer.

We report a covalent chemistry-based hepatocellular carcinoma (HCC)-specific extracellular vesicle (EV) purification system for early detection of HCC by performing digital scoring on the purified EVs. Earlier detection of HCC creates more opportunities for curative therapeutic interventions. EVs are present in circulation at relatively early stages of disease, providing potential opportunities for HCC early detection. We develop an HCC EV purification system (i.e., EV Click Chips) by synergistically integrating covalent chemistry-mediated EV capture/release, multimarker antibody cocktails, nanostructured substrates, and microfluidic chaotic mixers. We then explore the translational potential of EV Click Chips using 158 plasma samples of HCC patients and control cohorts. The purified HCC EVs are subjected to reverse-transcription droplet digital PCR for quantification of 10 HCC-specific mRNA markers and computation of digital scoring. The HCC EV-derived molecular signatures exhibit great potential for noninvasive early detection of HCC from at-risk cirrhotic patients with an area under receiver operator characteristic curve of 0.93 (95% CI, 0.86 to 1.00; sensitivity = 94.4%, specificity = 88.5%). Extracellular vesicles (EVs) are present in circulation at relatively early stages of disease, providing potential opportunities for early cancer diagnosis. Here, the authors report a covalent chemistry-based hepatocellular carcinoma (HCC)-specific EV purification system for early detection of HCC by performing digital scoring on the purified EVs.

Oligonucleotide-conjugated antibodies have gained importance for their use in protein diagnostics. The possibility to transfer the readout signal from the protein to the DNA level with an oligonucleotide-conjugated antibody increased the sensitivity of protein assays by orders of magnitude and enabled new multiplexing strategies. A bottleneck in the generation of larger oligonucleotide-conjugated antibody panels is the low conjugation yield between antibodies and oligonucleotides, as well as the lack of product purification methods. In this study, we combined a non-site-directed antibody conjugation technique using copper-free click chemistry with ion-exchange chromatography to obtain purified single and double oligonucleotide-conjugated antibodies. We optimized the click conjugation reaction of antibodies with oligonucleotides by evaluating crosslinker, reaction temperature, duration, oligonucleotide length, and secondary structure. As a result, we were able to achieve conjugation yields of 30% at a starting quantity as low as tens of nanograms of antibody, which makes the approach applicable for a wide variety of protein analytical assays. In contrast to previous non-site-directed conjugation methods, we also optimized the conjugation reaction for antibody specificity, confirmed by testing with knockout cell lines. The advantages of using single or double oligonucleotide-conjugated antibodies in regards to signal noise reduction are shown within immunofluorescence, proximity ligation assays, and single cell CITE-seq experiments.

The copper(I)-catalyzed azide−alkyne cycloaddition (CuAAC) reaction is considered to be the most representative ligation process within the context of the “click chemistry” concept. This CuAAC reaction, which yields compounds containing a 1,2,3-triazole core, has become relevant in the construction of biologically complex systems, bioconjugation strategies, and supramolecular and material sciences. Although many CuAAC reactions are performed under homogenous conditions, heterogenous copper-based catalytic systems are gaining exponential interest, relying on the easy removal, recovery, and reusability of catalytically copper species. The present review covers the most recently developed copper-containing heterogenous solid catalytic systems that use solid inorganic/organic hybrid supports, and which have been used in promoting CuAAC reactions. Due to the demand for 1,2,3-triazoles as non-classical bioisosteres and as framework-based drugs, the CuAAC reaction promoted by solid heterogenous catalysts has greatly improved the recovery and removal of copper species, usually by simple filtration. In so doing, the solving of the toxicity issue regarding copper particles in compounds of biological interest has been achieved. This protocol is also expected to produce a practical chemical process for accessing such compounds on an industrial scale.