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Approved antibody–drug conjugates (ADCs) remain constrained by a limited repertoire of payloads with restricted modes of action. Here, the authors present phosphoramidate-based self-immolative linker units that facilitate stable attachment in serum and traceless drug release in the target cell from aliphatic and aromatic alcohols with various modes of action.

While fluorophore-biomacromolecule systems are relatively well known, afterglow luminophore-biomacromolecule conjugates/complexes are rarely studied. Here, the authors report the development of a system with organic afterglow from luminophore-protein conjugates/complexes at freezing temperatures.

Late-stage specific and selective modifications of peptides and proteins at target residues under ambient conditions are the most facile routes to various bioconjugates. Here, the authors report an orthogonal modification of cysteine residues using alkyl thianthreium salts, which proceeds with excellent chemoselectivity and compatibility under mild conditions, introducing a diverse array of functional structures.

Protein PEGylation is routinely used to produce molecules with improved pharmacokinetic properties. However, despite their importance, the structure of PEGylated proteins has remained elusive. Now, the first crystal structure of a model β-sheet protein modified with a single PEG chain has been reported. NMR spectroscopy data indicates that the protein and PEG behave as independent domains.

Fundamental biophysical principles that govern particle inclusion in or exclusion from condensates are discovered, wherein arbitrarily large particles controllably partition into condensates given sufficiently strong condensate-particle interactions.

Antibody–drug conjugates have shown considerable promise for treating disease. However, in order to deliver their full potential, sophisticated site-specific conjugation technologies are needed. This Perspective provides an overview of the different methods used for the site-specific attachment of cytotoxic agents to antibodies.

Chiral communication can propagate in secondary structures within the effective intermolecular force (IMF) range but it is not known whether long-range chiral communication exists between tertiary peptide structures. Here, the authors use single-molecule force spectroscopy to investigate chiral interaction between DNA duplexes/triplexes and peptide coiled-coils and demonstrate chiral communication beyond the IMF distance.

Constructing polymer-based mimics on the surface of cells has potential to manipulate cell behavior, but precise control of grafting sites is challenging. Here, the authors report a method for site selected radical polymerization on cell surfaces by metabolic labelling.

Covalent inhibitors offer high potency but their potential is hindered by off-target reactivity. Now, an in vitro selection method has been developed to enable the discovery of covalent inhibitors from trillions of oligonucleotides endowed with the sulfur(VI) fluoride exchange chemistry. This strategy generates covalent inhibitors of protein–protein interactions with optimally balanced selectivity and reactivity.

Methods for direct covalent ligation of microorganism surfaces are scarce. Here, the authors developed a rapid electrochemical process for the direct covalent ligation and labelling of the surfaces of virus, bacteria and cells using N-methylluminol, a fully tyrosine-selective protein anchoring group.

Direct dissociation of nucleic acid duplex structures without heating or specific binding proteins is challenging. Here the authors use the cucurbit[7]uril-based host–guest system to construct a ligand-invasion pathway for controllable DNA hybridisation.

Reversible on/off switches for enzyme activity are foundational in nature but are challenging to design using tools of synthetic chemistry. Here the authors design chemical zymogens amenable for activation via biomolecular interactions.

Triphenylphosphonium ylides (Wittig reagents) that selectively react with sulfenic acids—a pivotal post-translational cysteine modification in redox biology—are developed. This bioconjugation method enables a site-specific proteome-wide stoichiometry analysis of S-sulfenylation, and visualization of redox-dependent changes in mitochondrial cysteine oxidation and the redox-triggered generation of triphenylphosphonium for the controlled delivery of small molecules to mitochondria.

Machine learning has now been shown to enable the de novo design of abiotic nuclear-targeting miniproteins. To achieve this, high-throughput experimentation was combined with a directed evolution-inspired deep-learning approach in which the molecular structures of natural and unnatural residues are represented as topological fingerprints. The designed miniproteins, called Mach proteins, are non-toxic and can efficiently deliver antisense cargo in mice.

Mitochondria are a source of reactive oxygen species, which can be exploited to induce the death of cancer cells. Here, the authors use nanoparticles that release camptothecin in a reactive oxygen species dependent manner, leading to cancer cell death.

Nanoparticles that access lymphatic vessels and are functionalized with degradable linkers, whose half-lives can be programmed, enable the controlled release of therapeutic cargo in different regions of the lymph nodes, allowing the targeting of otherwise difficult-to-reach lymphocyte subpopulations.

Amphiphilic protein-polymer conjugates remain largely unexplored due to synthetic protocols being complex. Here the authors explore an oxygen tolerant, photoinduced reversible-deactivated radical polymerization approach, which readily affords quantitative yields within 2 h and thus avoids damage to the secondary structure of the proteins.

Microcompartments with a temperature-responsive membrane are used to stably localize DNA-encoded files, which enables parallel, repeated polymerase-chain-reaction-based random access and DNA file sorting using fluorescent barcodes.

Methods for stabilizing enzymatic activity in the gastrointestinal tract are rarely investigated because of the difficulty in protecting proteins from an environment that promotes their digestion. Now, functionally diverse polymers have been conjugated to therapeutic enzymes, which lead to a substantial enhancement of their in vivo activity in the gastrointestinal tract.

Basic fibroblast growth factor (bFGF) is crucial for a range of diverse cellular processes, from wound healing to bone regeneration, yet is inherently unstable. This important biologic has now been covalently linked to a polymer that mimics the polysaccharide heparin to produce a conjugate that shows remarkable stability to a wide range of therapeutically and environmentally relevant stressors.

Synthetic polymer wires, which contain short oligonucleotides extending from each repeat, can assemble into predesigned routings on two- and three-dimensional DNA origami templates.

A cytocompatible controlled radical polymerization method has now been developed that initiates polymer synthesis directly on the surface of living cells. This method achieves significantly enhanced polymer grafting and enables active manipulation of cellular phenotypes.

Click chemistry enables efficient chemical labelling of small molecules in cells, providing a powerful method to visualize almost any biologically active compound. This versatile methodology can provide valuable information about the mechanisms of action of small molecules in various biological settings.

Bio-interface materials inspired by natural systems that respond efficiently to various external stimuli can dynamically regulate molecular interactions between biological entities and material surfaces. In this Review, Gomes and colleagues describe advances in bio-interface materials that may provide insights into cell behaviour, biofouling and the production of on-demand devices with medical applications, among others.

The fluorophore-modified glucan, TPE-6BG3 adopts an extended, random-coiled form in DMSO, which does not fluoresce. The morphology of the TPE-6BG3 chemosensor changes drastically to a dynamic globule in aqueous media. The dynamic, “induced-fit” globule selectively and sensitively recognizes the medicinally-useful tetrasaccharide, acarbose via glucan-saccharide coaggregation.

The mechanism of glycogenesis, initiated by glycogenin, involves three distinct kinetic phases, with the final phase involving a refining process where only glucose is tolerated as a substrate.

An enzymatic approach enables synthesis of a defined DNA sequence using TdT with reversibly tethered dNTPs.

Post-translational modifications expand the diversity of the proteome and regulate core biological processes. Chemical biology tools provide access to proteins bearing site-specific post-translational modifications, helping us to decipher their roles in health and disease.

Sulfur fluoride exchange (SuFEx) is a click reaction used to rapidly synthesize and discover functional molecules. In this Primer, Homer et al. discuss the essential elements of SuFEx operation, catalysis and SuFExable connective hubs and explore applications of SuFEx in drug development, polymer science and biochemistry.

Covalent inhibitors are a successful class of drugs, however, the optimization of targeted covalent inhibitors has challenges due to the need to increase non-covalent interactions and modulate reactivity. Here, the authors study the structure-reactivity-activity relationships of analogues of the EGFR inhibitor poziotinib, showing practical methods to characterize structure-activity relationships, providing insights into the origins of potency and highlighting the effect of chirality on covalent binding.

A cell-cultivable gel based on a polysaccharide “sacran” has been developed. Although the conventionally produced sacran gel does not show cell adhesion, it achieved compositing with collagen, which has cell adhesion, and showed its potential as a cell scaffold. The feature of this study is that the gelation of sacran was controlled by the addition of salt, and the composite with collagen was achieved for the first time.

Using polymerase chain reaction (PCR)-mediated recombination, we prepared single ribonucleic acid (RNA) chains containing bifunctional RNA sequences involving substrate binding and phosphorescent signaling. The prepared RNAs largely maintained the functionalities of the original aptamers even after bifunctionalization. We demonstrated that the bifunctionalized RNAs can be used as phosphorescent detection probes for the target protein. Therefore, we suggested that the PCR-mediated “one stroke drawing” is a promising strategy for the preparation of RNA detection probes.

An ethylene glycol-based hexa-block copolymer with six different temperature-responsive blocks was prepared via a reversible addition-fragmentation chain transfer (RAFT) polymerization. 2-(2-Methoxyethoxy)ethyl methacrylate (MEO₂MA) and oligo(ethylene glycol) methacrylate (OEGMA) were selected as the ethylene glycol-based monomers. Each block exhibits a different LCST in aqueous solution owing to their different OEGMA contents.

Cyclic polymers have a ring-like architecture and one of the most important consequences of this topology is the absence of any chain ends, which typically have a substantial impact on the physical properties of macromolecules. This Review Article discusses advances in the synthesis, purification and characterization of cyclic polymers and the potential applications they may prove useful for.

Tagging and manipulating biomolecules in living systems requires precisely tuned, biocompatible reactions. This Review focuses on recent advances in the development of bioorthogonal reactions, with an emphasis on how mechanistic insights have driven the field.

Permeation of model drugs with different molecular weights through a bioconjugated membrane having antigen–antibody complexes as reversible crosslinks was investigated in the absence and presence of a target antigen. The bioconjugated membrane regulated the drug permeation in response to the concentration of a target antigen. This paper focuses on the effect of the molecular size of the drugs on controlled permeability of the antigen-responsive membrane.

DNA undergoes large volume transition to organize several higher-order structures, including globular, rod-shaped, and ring-shaped (toroid) structures by polyion complexation with block copolymer comprising hydrophilic segment and polycations. This review discusses the origin of this versatile higher-order structure formation. The knowledge of underlying physical mechanisms might ultimately improve our understanding of the formation of hierarchically ordered structures in the nucleosomes and the operating principles governing how DNA functionality emerges, and also provide a solid strategy to prepare structured nonviral gene vectors.

It was found that a synthetic 24-mer β-annulus peptide, which participates in the formation of the dodecahedral internal skeleton of the tomato bushy stunt virus capsid, spontaneously self-assembled into artificial viral capsids with a size of 30–50 nm. The artificial viral capsids could be dressed up with gold nanoparticles, single-stranded DNA, coiled-coil spikes, and proteins by modifying with these molecules at the C-terminus of β-annulus peptides. The artificial viral capsids were notably stabilized by dressing up with human serum albumin and acquired enzymatic activity by dressing up with ribonuclease.

Our recent studies on the nano- and micro-structured molecule-responsive hydrogels are summarized. The nano- and micro-structured molecule-responsive hydrogels exhibited rapid swelling/shrinkage behavior in response to a target molecule based on the association/dissociation of molecular complexes that act as crosslinkers. In addition, these hydrogels showed smart functions, such as autonomous molecule-responsive microchannel flow regulation and highly sensitive detection of a target molecule. The smart functions of nano- and micro-structured molecule-responsive hydrogels can provide tools for constructing sensors, microdevices and smart biomaterials.

Developing effective inhibitors of the DNA repair enzyme tyrosyl-DNA phosphodiesterase 1 (TDP1) is challenging because of the enzyme’s shallow catalytic pocket and non-specific substrate binding interactions. Here, the authors use Sulfur (VI) fluoride exchange chemistries to prepare covalent TDP1-bound binders showing site-specific covalent bonds with the Y204 residue that position DNA.