Trends in Chemistry

DNA-scaffolded catalysis A longstanding goal in supramolecular chemistry has been to enhance the functionality of abiotic catalysts by attaching them to 3D scaffolds, analogous to enzyme active sites. Recent advances in DNA synthesis, DNA sequencing, and DNA-compatible chemical reactions open opportunities to enhance the function and accelerate the discovery of abiotic catalysts by interfacing them with DNA. Here we highlight the ways in which DNA has been merged with abiotic catalysis, including stereoselectivity, regioselectivity, switchability, and scaffolding of multiple reaction components. Furthermore, we describe how the programmable self-assembly and information-encoding properties of DNA enable high-throughput screening of abiotic chemical reactions. We discuss key advances, challenges, and opportunities to harness the potential of synthetic DNA as a scaffold for abiotic catalysis.

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Online now: Iodonitrene-mediated synthesis of NH-aziridines

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Functional bioconjugates for precision delivery of nucleic acid therapeutics Nucleic acid therapeutics such as small interfering RNAs (siRNAs) and antisense oligonucleotides (ASOs) have become powerful tools to modulate gene expression, but their clinical potential is limited by delivery challenges. We explore how chemistry-driven bioconjugates, especially covalent conjugates of oligonucleotides with targeting ligands, are among the most promising strategies to overcome systemic delivery barriers. Rational bioconjugation can address issues of renal clearance, endosomal entrapment, and off-target toxicity by enabling cell-specific uptake and controlled intracellular release. Recent advances in organ-targeted conjugates for the liver, kidney, brain, and lung highlight the versatility of this approach. Machine learning (ML) techniques applied to ligand and linker design and identification of new tissue target sites are crucial for advancing the precise delivery of nucleic acid therapeutics.

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Insights into G-quadruplexes and i-motifs in MYD88 G-quadruplexes (G4s) and i-motifs (iMs) are noncanonical DNA structures that regulate transcription. Recent structural analysis of an iM within the MYD88 promoter reveals its stability and interaction with CTCF, suggesting secondary-structure-mediated transcriptional control. Understanding G4/iM dynamics may enable selective therapeutic targeting of DNA folding in immune regulation.

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Nucleic acid-guided protein-empowered aquatic contaminants sensing The rapid evolution of nucleic acid-guided proteins (e.g., CRISPR/Cas12a, Argonaute) has positioned them as transformative tools for aquatic contaminant sensing. Their programmability, compatibility with diverse signal transducers, and field-deployable designs enable unprecedented on-site environmental monitoring. This review outlines the fundamental mechanisms of nucleic acid (NA)-guided proteins, critically analyzes implementation strategies (including field-deployable platforms), and systematically highlights their applications in the sensing of aquatic pollutants. We further discuss current challenges and future research directions to further advance multiplexing, sensitivity enhancement, artificial intelligence (AI)-assisted engineering, and integrated on-site detection areas. By providing comprehensive insights into this emerging field, we hope that this review will serve as an important resource for researchers developing next-generation NA-guided proteins-based environmental surveillance tools to address ‘One Health’ challenges at aquatic interfaces.

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Rational design of therapeutic RNA molecules Therapeutic RNA molecules have undergone a profound transformation, evolving from limited application of small RNAs to a diverse array of RNA types that target multiple levels of cellular regulation in treating various diseases previously untreatable. This review introduces a general design framework that integrates chemical synthesis, structural biology, and computational approaches to overcome key challenges in RNA therapeutics. We explore how this framework enhances RNA stability, minimizes undesired immunogenicity, improves therapeutic potency, and enables targeted delivery. We also highlight a prime example of this synergy: the rapid development and success of mRNA vaccines during the recent pandemic. This framework serves as a guide for researchers, enabling the creation of more effective, safer, and highly specific RNA-based medicines for a wide spectrum of diseases.

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Steroids under voltage: unlocking reactivity with electrochemistry Steroids are ubiquitous natural compounds that play essential physiological roles in both plants and animals. Owing to their diverse biological activities, including anti-inflammatory, antitumor, antiviral, and antimicrobial effects, steroidal compounds have found widespread therapeutic uses in the treatment of numerous clinical conditions. Unsurprisingly, the global steroid market is valued at approximately US$4 billion. Despite their broad impact in chemical research and the pharmaceutical industry, the synthesis of steroids remains challenging due to the structural complexity and limited availability of efficient synthetic methodologies. This review highlights recent advances in electrochemically enabled approaches for steroid activation and functionalization, aiming to inspire innovative and sustainable strategies for steroid manipulation and production.

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Electrospun mesh electrodes advance paper-based nucleic acid detection Detection of nucleic acids is essential for modern diagnostics, but standard polymerase chain reaction (PCR) and fluorescence assays are costly and infrastructure-dependent. Paper-based electrochemical devices (ePADs) offer low-cost, portable alternatives but face electrode architecture limitations. A new platform, FiberSens, eliminates complex functionalization, providing a scalable, clinically-relevant solution for decentralized healthcare, veterinary, and environmental applications.

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Online now: Amino acid tailoring strategies in peptide natural product biosynthesis

Electrosynthesis unleashed: green pathways to natural product synthesis Electrosynthesis is reshaping natural product total synthesis by replacing stoichiometric oxidants and reductants, reducing waste, and enabling orthogonal reactivity. We highlight recent advances that demonstrate mediator and catalyst platforms alongside sustainability metrics, including anodic functionalization, reductive couplings, and electrochemical oxidative dearomatization-induced (ODI)-[5+2] cascades. These strategies deliver safer, scalable, and low-carbon synthetic routes, extending access to targets previously unattainable by conventional methods.

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Non-carbohydrate syntheses of nucleoside analogues Nucleoside analogues (NAs) continue to be a rich source of antiviral and anticancer drug leads and critical components of oligonucleotide therapeutics (ONTs). To support drug development, significant effort has been directed towards their synthesis. For several decades, these processes relied heavily on carbohydrates as key chiral building blocks. While carbohydrates possess structural and stereochemical features common to nucleosides, significant protecting group and redox manipulations are required to produce many modern NA drugs and ONTs. This can limit comprehensive structure–activity relationship studies and challenge process chemistry efforts. Recent advances now enable production of NAs from non-carbohydrate materials and create opportunities for accelerating NA and ONT discovery. This review will summarize and showcase these methods and their application in NA synthesis.

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🧪 Check out the October issue of Trends in Chemistry!
Our cover article and artwork comes from Pil Seok Chae & team at Hanyang University. Their Review highlights novel design strategies for pendant-bearing detergents to investigate membrane proteins.
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Size-based separation of bioactive molecules by membrane technology: beyond molecular weight Production of high-purity biomacromolecules with high yield is a core issue for the biopharmaceutical sector. Membrane technology, a non-thermal process based on size exclusion, is a primary technique for bioseparation. Despite its broad application, membrane technology still faces many challenges in the accurate isolation of biomolecules. The flexibility of biomolecular conformations causes dynamic size changes and irregular transmembrane transport. Meanwhile, the inhomogeneous distribution of membrane pore size and suboptimal operational conditions substantially compromise size-exclusion performance, especially for species with similar molecular weight. This article aims to identify the causes of low separation precision in biomolecule purification and reviews recent technological advances in fine separation methods by analyzing bio-solution characteristics, membrane physicochemical properties, and industrial process design.

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DNA-compatible chemistry for DNA-encoded libraries and beyond DNA-encoded libraries (DELs) have emerged as a critical technology for rapid hit identification in drug discovery. The effectiveness of DEL selection fundamentally depends on the chemical diversity present within the library. As DNA-compatible chemistry plays a central role in expanding both the chemical space and molecular diversity of DELs, this area has seen significant advancements in recent years. Additionally, research in DNA-compatible chemistry and bioconjugation chemistry demonstrates a synergistic relationship. This review focuses on the most recent developments in DNA-compatible chemistry and highlights its expanding applications beyond traditional library construction. Current synthetic challenges are examined, and potential directions for future research and development are explored.

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Smart lipid nanoparticles: the chemistry driving targeted therapeutics Recently, lipid nanoparticles (LNPs) have transformed drug delivery, particularly for nucleic acid vaccines and gene therapy. LNPs provide biocompatibility, enhanced bioavailability, and controlled release. However, nonspecific distribution remains a limitation for conventional LNPs. This review highlights the evolution of targeted LNPs (tLNPs) as precision drug delivery systems, with emphasis on recent innovations in surface functionalization, lipid composition tuning, and organ-specific delivery. Unlike prior reviews focused on general LNP formulations, we explore active targeting strategies, including ligand conjugation and structure-driven targeting, that redefine therapeutic precision and reduce off-target effects. This review presents a comprehensive overview of how tLNPs are advancing towards clinical applications across immunotherapy, gene editing, and personalized medicine.

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Online now: Adenosine deaminase: structure–activity relationships and harnessing biocatalysis to access purine nucleoside analogues

Main group materials syntheses at low temperatures This review describes three general approaches for the mild (

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Self-assembly of (poly)peptide-oligonucleotide conjugates: from orthogonality to emergence Peptides and DNA both display characteristic self-assembly motifs which underpin the spectacularly varied and functional nanostructures of biology. Ea…

Thanks to @jesspanch.bsky.social at Trends in Chemistry for handling this review article on DNA-peptide self-assembly which is just out. This outlook is going to frame some more papers you'll see coming out my lab over the next year or so.
www.sciencedirect.com/science/arti...

Self-assembly of (poly)peptide-oligonucleotide conjugates: from orthogonality to emergence Peptides and DNA both display characteristic self-assembly motifs which underpin the spectacularly varied and functional nanostructures of biology. Each of these has been harnessed by chemists to develop peptide and DNA nanotechnologies separately, but in nature different biomolecules interact both directly and indirectly in support of the larger cell and organism. Peptide-oligonucleotide conjugates (POCs) have now emerged as building blocks in nanotechnology. We review recent advances in the self-assembly of POCs, through the lens of increasingly developed complexity. While the simplest systems result in orthogonal or hierarchical self-assembly, more advanced examples introduce complementary or competitive aspects, and those closest to nature feature emergent properties. Complex, dynamic nanosystems such as these give us new insights into how life builds structures from biomolecules.

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Transition metal catalysis drives innovative activity-based sensing systems Through mechanistic understanding, transition metal catalysis has evolved into a key component of the organic chemists’ toolbox. Improvements in ligand design continue to push the boundaries of applications beyond targeted synthesis. This Forum contextualizes how mechanistic insight has influenced recent developments in transition metal-based molecular sensing.

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Asymmetric partial reductions of pyridines The asymmetric partial reduction (APR) of substituted pyridines represents a direct and versatile strategy to access chiral dihydropyridines (DHPs) and tetrahydropyridines (THPs), which are present in many natural products and active pharmaceutical ingredients (APIs). However, this methodology remains significantly underdeveloped when compared with the numerous exhaustive asymmetric reductions of pyridines to fully saturated piperidines, and is currently still limited to the synthesis of THPs. In this opinion, we highlight the benefits, challenges, and current scope of asymmetric partial pyridine reductions, emphasizing prospective future directions to address significant gaps in the current literature.

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MS-based spatial proteomics: deciphering tissue microenvironment by bridging MS imaging and large-scale proteomics Mass spectrometry (MS)-based spatial proteomics combines molecular profiling with histological context, allowing proteins and peptides to be mapped within tissues. Evolving from early immunostaining to advanced mass spectrometry imaging (MSI), multiplex immuno-MSI, and spatially resolved proteomics, this field now addresses significant challenges in biology and medicine. In this review, we outline various approaches and methodologies from foundational methods to recent advances including matrix-assisted laser desorption/ionization (MALDI) immunohistochemistry (IHC) and spatially resolved large-scale proteomics. Examples from oncology and neuroscience illustrate the growing impact of spatial proteomics, while emerging directions such as single-cell and subcellular workflows, tissue-expansion strategies, and integrated multi-omics foreshadow a future of comprehensive tissue atlases at unprecedented resolution.

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Uncovering RNA grammar in driving synthetic condensates Ribonucleoprotein complexes are key players in driving natural cellular condensates. Recent studies have further shown that RNA itself, via highly modular and programmable self-assembly and multivalent interactions, can also function as scaffold for engineering synthetic condensates. These synthetic RNA-driven condensates exhibit unique molecular and material properties in compartmentalization, target selectivity, switchability, and spatial controllability, together with potential functions as chemical and/or genetically encodable tools in reaction control, biosensing, RNA network regulation, origin of life and artificial cell studies, and therapeutics. Here, we describe the molecular features, design principles, and physical and material properties of these emerging RNA-driven synthetic condensates, as well as the potential applications and current trends in the field.

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Online now: Nitrogen atom transposition of pyridine

Advances in nontraditional luminescent gel soft materials Nontraditional organic chromophores have gained significant attention as promising alternatives to conventional π-conjugated luminescent materials. These innovative nontraditional systems circumvent the intrinsic limitations of traditional chromophores by leveraging supramolecular interactions (e.g., hydrogen bonding, π–π stacking) to achieve tunable photoluminescence through precisely engineered through-space charge transfer (TSCT) and clusteroluminogenic assemblies. Their unique combination of structural flexibility, intrinsic biocompatibility, and stimulus-responsive characteristics presents transformative potential across diverse applications of optoelectronic devices, chemical sensing platforms, and biomedical engineering. However, practical implementation at scale remains constrained by insufficient solution-processability and inadequate mechanical robustness. Emerging strategies integrating these nontraditional chromophores with gel-based matrices demonstrate particular promise in addressing technological bottlenecks. This review will examine recent breakthroughs in gel soft materials incorporating nontraditional organic chromophores.

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Online now: Expanding epitranscriptomics to non-enzymatic RNA modifications