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Nucleobases control the assembly of DNA, RNA, etc. due to hydrogen bond complementarity. By combining these unique molecules with state-of-the-art synthetic polymers, it is possible to form nanoparticles whose self-assembly behavior could be altered under orthogonal stimuli (pH and temperature). Herein, we report the synthesis of cytosine-containing nanoparticles via aqueous reversible addition-fragmentation chain transfer polymerization-induced self-assembly. A poly(N-acryloylmorpholine) macromolecular chain transfer agent (mCTA) was chain-extended with cytosine acrylamide, and a morphological phase diagram was constructed. By exploiting the ability of cytosine to form dimers via hydrogen bonding, the self-assembly behavior of cytosine-containing polymers was altered when performed under acidic conditions. Under these conditions, stable nanoparticles could be formed at longer polymer chain lengths. Furthermore, the resulting nanoparticles displayed different morphologies compared to those at pH 7. Additionally, particle stability post-assembly could be controlled by varying pH and temperature. Finally, small-angle X-ray scattering was performed to probe their dynamic behavior under thermal cycling.
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Citosina , Enlace de Hidrógeno , Nanopartículas , Citosina/química , Concentración de Iones de Hidrógeno , Nanopartículas/química , Temperatura , Polimerizacion , Polímeros/químicaRESUMEN
The synthesis of artificial sequence-defined polymers that match and extend the functionality of proteins is an important goal in materials science. One way of achieving this is to program a sequence of chemical reactions between precursor building blocks by means of attached oligonucleotide adapters. However, hydrolysis of the reactive building blocks has so far limited the length and yield of product that can be obtained using DNA-templated reactions. Here, we report an architecture for DNA-templated synthesis in which reactants are tethered at internal abasic sites on opposite strands of a DNA duplex. We show that an abasic site within a DNA duplex can protect a nearby thioester from degradation, significantly increasing the yield of a DNA-templated reaction. This protective effect has the potential to overcome the challenges associated with programmable, sequence-controlled synthesis of long non-natural polymers by extending the lifetime of the reactive building blocks.
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Replicación del ADN , ADN , ADN/metabolismo , Oligonucleótidos , PolímerosRESUMEN
The contents of biological cells are retained within compartments formed of phospholipid membranes. The movement of material within and between cells is often mediated by the fusion of phospholipid membranes, which allows mixing of contents or excretion of material into the surrounding environment. Biological membrane fusion is a highly regulated process that is catalyzed by proteins and often triggered by cellular signaling. In contrast, the controlled fusion of polymer-based membranes is largely unexplored, despite the potential application of this process in nanomedicine, smart materials, and reagent trafficking. Here, we demonstrate triggered polymersome fusion. Out-of-equilibrium polymersomes were formed by ring-opening metathesis polymerization-induced self-assembly and persist until a specific chemical signal (pH change) triggers their fusion. Characterization of polymersomes was performed by a variety of techniques, including dynamic light scattering, dry-state/cryogenic-transmission electron microscopy, and small-angle X-ray scattering (SAXS). The fusion process was followed by time-resolved SAXS analysis. Developing elementary methods of communication between polymersomes, such as fusion, will prove essential for emulating life-like behaviors in synthetic nanotechnology.
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Nanotecnología , Polímeros , Dispersión del Ángulo Pequeño , Difracción de Rayos X , Polímeros/química , Microscopía Electrónica de TransmisiónRESUMEN
The decoration of 2D nanostructures using heteroepitaxial growth is of great importance to achieve functional assemblies employed in biomedical, electrical, and mechanical applications. Although the functionalization of polymers before self-assembly has been investigated, the exploration of direct surface modification in the third dimension from 2D nanostructures has, to date, been unexplored. Here, we used living crystallization-driven self-assembly to fabricate poly(ε-caprolactone)-based 2D platelets with controlled size. Importantly, surface modification of the platelets in the third dimension was achieved by using functional monomers and light-induced polymerization. This method allows us to selectively regulate the height and fluorescence properties of the nanostructures. Using this approach, we gained unprecedented spatial control over the surface functionality in the specific region of complex 2D platelets.
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DNA-polymer hybrids have been attracting interest as adaptable functional materials by combining the stability of polymers with DNA nanotechnology. Both research fields have in common the capacity to be precise, versatile, and tunable, a prerequisite for creating powerful tools which can be easily tailored and adapted for bio-related applications. However, the conjugation of hydrophilic DNA with hydrophobic polymers remains challenging. In recent years, polymerization-induced self-assembly (PISA) has attracted significant attention for constructing nano-objects of various morphologies owing to the one-step nature of the process, creating a beneficial method for the creation of amphiphilic DNA-polymer nanostructures. This process not only allows pure DNA-polymer-based systems to be produced but also enables the mixture of other polymeric species with DNA conjugates. Here, we present the first report of a DNA-PEG corona nano-object's synthesis without the addition of an external photoinitiator or photocatalyst via photo-PISA. Furthermore, this work shows the use of DNA-macroCTA, which was first synthesized using a solid-support method resulting in high yields, easy upscaling, and no need for HPLC purification. In addition, to the formation of DNA-polymer structures, increasing the nucleic acid loading of assemblies is of great importance. One of the most intriguing phenomena of DNA is the hybridization of single-stranded DNA with a second strand, increasing the nucleic acid content. However, hybridization of DNA in a particle corona may destabilize the nanomaterial due to the electrostatic repulsive force on the DNA corona. Here, we have investigated how changing the DNA volume fraction in hybrid DNA-polymer self-assembled material affects the morphology. Moreover, the effect of the corona composition on the stability of the system during the hybridization was studied. Additionally, the hybridization chain reaction was successfully applied as a new method to increase the amount of DNA on a DNA-based nano-object without disturbing the morphology achieving a fluorescence signal amplification.
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Nanoestructuras , Ácidos Nucleicos , Nanoestructuras/química , ADN/química , Nanotecnología , Polímeros/químicaRESUMEN
The design and fabrication of synthetic self-assembled systems that can mimic some biological features require exquisitely sophisticated components that make use of supramolecular interactions to attain enhanced structural and functional complexity. In nature, nucleobase interactions play a key role in biological functions in living organisms, including transcription and translation processes. Inspired by nature, scientists are progressively exploring nucleobase synthons to create a diverse range of functional systems with a plethora of nanostructures by virtue of molecular-recognition-directed assembly and flexible programmability of the base-pairing interactions. To that end, nucleobase-functionalized molecules and macromolecules are attracting great attention because of their versatile structures with smart and adaptive material properties such as stimuli responsiveness, interaction with external agents, and ability to repair structural defects. In this regard, a range of nucleobase-interaction-mediated hierarchical self-assembled systems have been developed to obtain biomimetic materials with unique properties. For example, a new "grafting to" strategy utilizing complementary nucleobase interactions has been demonstrated to temporarily control the functional group display on micellar surfaces. In a different approach, complementary nucleobase interactions have been explored to enable morphological transitions in functionalized diblock copolymer assembly. It has been demonstrated that complementary nucleobase interactions can drive the morphological transformation to produce highly anisotropic nanoparticles by controlling the assembly processes at multiple length scales. Furthermore, nucleobase-functionalized bottle brush polymers have been employed to generate stimuli-responsive hierarchical assembly. Finally, such interactions have been exploited to induce biomimetic segregation in polymer self-assembly, which has been employed as a template to synthesize polymers with narrow polydispersity. It is evident from these examples that the optimal design of molecular building blocks and precise positioning of the nucleobase functionality are essential for fabrication of complex supramolecular assemblies. While a considerable amount of research remains to be explored, our studies have demonstrated the potential of nucleobase-interaction-mediated supramolecular assembly to be a promising field of research enabling the development of biomimetic materials.This Account summarizes recent examples that employ nucleobase interactions to generate functional biomaterials by judicious design of the building blocks. We begin by discussing the molecular recognition properties of different nucleobases, followed by different strategies to employ nucleobase interactions in polymeric systems in order to achieve self-assembled nanomaterials with versatile properties. Moreover, some of their prospective biological/material applications such as enhanced drug encapsulation, superior adhesion, and fast self-healing properties facilitated by complementary nucleobase interactions are emphasized. Finally, we identify issues and challenges that are faced by this class of materials and propose future directions for the exploration of functional materials with the aim of promoting the development of nucleobase-functionalized systems to design the next generation of biomaterials.
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Biomimética , Polímeros , Materiales Biocompatibles , Sustancias Macromoleculares/química , Polímeros/química , Estudios ProspectivosRESUMEN
Aliphatic polyesters are widely studied due to their excellent properties and low-cost production and also because, in many cases, they are biodegradable and/or recyclable. Therefore, expanding the range of available aliphatic polyesters is highly desirable. This paper reports the synthesis, morphology, and crystallization kinetics of a scarcely studied polyester, polyheptalactone (PHL). First, we synthesized the η-heptalactone monomer by the Baeyer-Villiger oxidation of cycloheptanone before several polyheptalactones of different molecular weights (in the range between 2 and 12 kDa), and low dispersities were prepared by ring-opening polymerization (ROP). The influence of molecular weight on primary nucleation rate, spherulitic growth rate, and overall crystallization rate was studied for the first time. All of these rates increased with PHL molecular weight, and they approached a plateau for the highest molecular weight samples employed here. Single crystals of PHLs were prepared for the first time, and hexagonal-shaped flat single crystals were obtained. The study of the crystallization and morphology of PHL revealed strong similarities with PCL, making PHLs very promising materials, considering their potential biodegradable character.
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Poliésteres , Cinética , Cristalización , Poliésteres/química , PolimerizacionRESUMEN
Herein, a library of trifluoroethyl substituted aminomaleimide derivatives are reported with small size and enhanced emissions in both solution and solid-state. A diCH2 CF3 substituted aminochloromaleimide exhibits the most efficient dual-state emission (Φf >50 % in solution and solid-state), with reduced quenching from protic solvents. This is attributed to the reduction of electron density on the maleimide ring and suppressed π-π stacking in the solid-state. This mechanism was explored in-depth by crystallographic analysis, and modelling of the electronic distribution of HOMO-LUMO isosurfaces and NCI plots. Hence, these dual-state dyes overcome the limitations of single-state luminescence and will serve as an important step forward for this rapidly developing nascent field.
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The past decades have seen significant research effort in the field of polymers for a range of biomedical applications, driven by the promising prospect of these materials for realizing next generation therapeutics in the clinic. In this regard, it is widely accepted that polymer properties such as chemistry, charge, and block composition, as well as properties of their self-assemblies including size, shape, surface chemistry, and biodegradation, all influence and direct their interactions with cells and biological membranes. In particular, polymer hydrophobicity is a property of interest, with growing evidence demonstrating the significant impact that hydrophobic interactions with lipid membranes and proteins can have on biomaterial application efficacy within the body. However, to date, this phenomenon has been relatively underexplored, and therefore there exists no clear universal understanding to direct polymer design. In this Perspective, we highlight important contributions to this field, focusing on seminal studies which investigate experimentally and theoretically how incorporation of hydrophobic moieties within polymer systems can influence their ultimate properties when used in biomedical applications. In this way, we aim to signify future directions in the design of highly performing polymers for biomedicine, making a case for the importance of standardized computational modeling to achieve widely applicable conclusions and facilitate future translational efforts.
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Materiales Biocompatibles , Polímeros , Interacciones Hidrofóbicas e Hidrofílicas , ProteínasRESUMEN
Aqueous ring-opening metathesis polymerization (ROMP) is a powerful tool for polymer synthesis under environmentally friendly conditions, functionalization of biomacromolecules, and preparation of polymeric nanoparticles via ROMP-induced self-assembly (ROMPISA). Although new water-soluble Ru-based metathesis catalysts have been developed and evaluated for their efficiency in mediating cross metathesis (CM) and ring-closing metathesis (RCM) reactions, little is known with regards to their catalytic activity and stability during aqueous ROMP. Here, we investigate the influence of solution pH, the presence of salt additives, and catalyst loading on ROMP monomer conversion and catalyst lifetime. We find that ROMP in aqueous media is particularly sensitive to chloride ion concentration and propose that this sensitivity originates from chloride ligand displacement by hydroxide or H2O at the Ru center, which reversibly generates an unstable and metathesis inactive complex. The formation of this Ru-(OH)n complex not only reduces monomer conversion and catalyst lifetime but also influences polymer microstructure. However, we find that the addition of chloride salts dramatically improves ROMP conversion and control. By carrying out aqueous ROMP in the presence of various chloride sources such as NaCl, KCl, or tetrabutylammonium chloride, we show that diblock copolymers can be readily synthesized via ROMPISA in solutions with high concentrations of neutral H2O (i.e., 90 v/v%) and relatively low concentrations of catalyst (i.e., 1 mol %). The capability to conduct aqueous ROMP at neutral pH is anticipated to enable new research avenues, particularly for applications in biological media, where the unique characteristics of ROMP provide distinct advantages over other polymerization strategies.
RESUMEN
Understanding, predicting, and controlling the self-assembly behavior of stimuli-responsive block copolymers remains a pertinent challenge. As such, the copolymer blending protocol provides an accessible methodology for obtaining a range of intermediate polymeric nanostructures simply by blending two or more block copolymers in the desired molar ratio to target specific stimuli-responsiveness. Herein, thermoresponsive diblock copolymers are blended in various combinations to investigate whether the resultant cloud point temperature can be modulated by simple manipulation of the molar ratio. Thermoresponsive amphiphilic diblock copolymers composed of statistical poly(n-butyl acrylate-co-N,N-dimethylacrylamide) core-forming blocks and four different thermoresponsive corona-forming blocks, namely poly(diethylene glycol monomethyl ether methacrylate) (p(DEGMA)), poly(N-isopropylacrylamide), poly(N,N-diethylacrylamide), and poly(oligo(ethylene glycol) monomethyl ether methacrylate) (p(OEGMA)) are selected for evaluation. Using variable temperature turbidimetry, the thermoresponsive behavior of blended diblock copolymer self-assemblies is assessed and compared to the thermoresponsive behavior of the constituent pure diblock copolymer micelles to determine whether comicellization is achieved and more significantly, whether the two blended corona-forming thermoresponsive blocks exhibit cooperative behavior. Interestingly, blended diblock copolymer micelles composed of p(DEGMA)/p(OEGMA) mixed coronae display cooperative behavior, highlighting the potential of copolymer blending for the preparation of stimuli-responsive nanomaterials in applications such as oil recovery, drug delivery, biosensing, and catalysis.
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Micelas , Polímeros/química , Polímeros/síntesis química , Acrilamidas/química , Acrilatos/química , Resinas Acrílicas/química , Metacrilatos/química , Polietilenglicoles/química , Polimerizacion , Propiedades de Superficie , TemperaturaRESUMEN
Polymer-drug conjugates have received considerable attention over the last decades due to their potential for improving the clinical outcomes for a range of diseases. It is of importance to develop methods for their preparation that have simple synthesis and purification requirements but maintain high therapeutic efficacy and utilize macromolecules that can be cleared via natural excretory pathways upon breakdown. Herein, the combination of ring-opening polymerization (ROP) and reversible addition-fragmentation chain-transfer (RAFT) polymerization is described for the straightforward synthesis of amphiphilic, stimuli-responsive, biodegradable, and highly functionalizable hyperbranched polymers. These unimolecular nanoparticles demonstrate a versatile platform for the synthesis of polymer-drug conjugates owing to the inclusion of a Boc-protected polycarbonate moiety in either a block or random copolymer formation. A proof-of-concept study on the complexation of the poorly water-soluble antimicrobial drug usnic acid results in polymer-drug complexes with powerful antimicrobial properties against gram-positive bacteria. Therefore, this work highlights the potential of amphiphilic and biodegradable hyperbranched polymers for antimicrobial applications.
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Antiinfecciosos , Benzofuranos , Antiinfecciosos/farmacología , Polimerizacion , PolímerosRESUMEN
Cylinders are fascinating structures with uniquely high surface area, internal volume, and rigidity. On the nanoscale, a broad range of applications have demonstrated advantageous behavior of cylindrical micelles or bottlebrush polymers over traditional spherical nano-objects. In the past, obtaining pure samples of cylindrical nanostructures using polymer building blocks via conventional self-assembly strategies was challenging. However, in recent years, the development of advanced methods including polymerization-induced self-assembly, crystallization-driven self-assembly, and bottlebrush polymer synthesis has facilitated the easy synthesis of cylindrical nano-objects at industrially relevant scales. In this Perspective, we discuss these techniques in detail, highlighting the advantages and disadvantages of each strategy and considering how the cylindrical nanostructures that are obtained differ in their chemical structure, physical properties, colloidal stability, and reactivity. In addition, we propose future challenges to address in this rapidly expanding field.
RESUMEN
The dynamic interactions of membranes, particularly their fusion and fission, are critical for the transmission of chemical information between cells. Fusion is primarily driven by membrane tension built up through membrane deformation. For artificial polymersomes, fusion is commonly induced via the external application of a force field. Herein, fusion-promoted development of anisotropic tubular polymersomes (tubesomes) was achieved in the absence of an external force by exploiting the unique features of aqueous ring-opening metathesis polymerization-induced self-assembly (ROMPISA). The out-of-equilibrium tubesome morphology was found to arise spontaneously during polymerization, and the composition of each tubesome sample (purity and length distribution) could be manipulated simply by targeting different core-block degrees of polymerization (DPs). The evolution of tubesomes was shown to occur via fusion of "monomeric" spherical polymersomes, evidenced most notably by a step-growth-like relationship between the fraction of tubular to spherical nano-objects and the average number of fused particles per tubesome (analogous to monomer conversion and DP, respectively). Fusion was also confirmed by Förster resonance energy transfer (FRET) studies to show membrane blending and confocal microscopy imaging to show mixing of the polymersome lumens. We term this unique phenomenon polymerization-induced polymersome fusion, which operates via the buildup of membrane tension exerted by the growing polymer chains. Given the growing body of evidence demonstrating the importance of nanoparticle shape on biological activity, our methodology provides a facile route to reproducibly obtain samples containing mixtures of spherical and tubular polymersomes, or pure samples of tubesomes, of programmed length. Moreover, the capability to mix the interior aqueous compartments of polymersomes during polymerization-induced fusion also presents opportunities for its application in catalysis, small molecule trafficking, and drug delivery.
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Complejos de Coordinación/síntesis química , Polímeros/síntesis química , Anisotropía , Complejos de Coordinación/química , Transferencia Resonante de Energía de Fluorescencia , Estructura Molecular , Tamaño de la Partícula , Polimerizacion , Polímeros/química , Propiedades de SuperficieRESUMEN
Fiber-like micelles based on biodegradable and biocompatible polymers exhibit considerable promise for applications in nanomedicine, but until recently no convenient methods were available to prepare samples with uniform and controllable dimensions and spatial control of functionality. "Living" crystallization-driven self-assembly (CDSA) is a seeded growth method of growing importance for the preparation of uniform 1D and 2D core-shell nanoparticles from a range of crystallizable polymeric amphiphiles. However, in the case of poly(l-lactide) (PLLA), arguably the most widely utilized biodegradable polymer as the crystallizable core-forming block, the controlled formation of uniform fiber-like structures over a substantial range of lengths by "living" CDSA has been a major challenge. Herein, we demonstrate that via simple modulation of the solvent conditions via the addition of trifluoroethanol (TFE), DMSO, DMF and acetone, uniform fiber-like nanoparticles from PLLA diblock copolymers with controlled lengths up to 1 µm can be prepared. The probable mechanism involves improved unimer solvation by a reduction of hydrogen bonding interactions among PLLA chains. We provide evidence that this minimizes undesirable unimer aggregation which otherwise favors self-nucleation that competes with epitaxial crystallization from seed termini. This approach has also allowed the formation of well-defined segmented block comicelles with PLLA cores via the sequential seeded-growth of PLLA block copolymers with different corona-forming blocks.
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Resinas Acrílicas/química , Micelas , Nanopartículas/química , Poliésteres/química , Cristalización , Enlace de Hidrógeno , Nanopartículas/ultraestructura , Tamaño de la Partícula , Solubilidad , SolventesRESUMEN
Nanomedicine is a promising strategy for improving clinical outcomes for cancer therapies, by improving drug efficacy through enhanced delivery to disease sites. It is of importance for ultimate clinical success to consider the contributing factors to achieving this goal, such as size, chemistry, and functionality of nanoparticle delivery systems, and how these parameters influence tumor localization and uptake. This Topical Review will first discuss the evolution and progress of nanoparticles for cancer drug delivery and the current challenges that remain to be addressed. Strategies for overcoming the limitations of passive targeting through active targeting approaches, and the current state of such nanomedicines in the clinic will be highlighted. Finally, novel approaches toward the design of active targeted nanoparticles building on our growing understanding of nanobio interactions are considered, in order to shed light on future design considerations for accelerating clinical translation of nanomedicines.
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Portadores de Fármacos/química , Diseño de Fármacos , Nanomedicina/métodos , Nanopartículas/química , Animales , HumanosRESUMEN
The selectivity of nucleic acid hybridisation can be exploited to template chemical reactions, enabling materials discovery by chemical evolution. However, to date the range of reactions that can be used has been limited to those that are compatible with aqueous media, since the addition of organic co-solvents can have a large impact on the stability of nucleic acid duplexes. Peptide nucleic acids (PNAs) are promising in this regard because previous studies have suggested they may be stable as duplexes in high organic content solvent mixtures. Here, we use micro-differential scanning calorimetry (micro-DSC) to confirm for the first time that double-stranded PNA (dsPNA) is stable in N,N-dimethylformamide (DMF)/water mixtures up to 95 vol% DMF. Using fluorescence, we corroborate these results and show that the isothermal annealing of PNA in high DMF content solution is also rapid. These findings suggest that PNA could enable the use of a range of water-sensitive chemistries in nucleic acid templating applications.
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Ácidos Nucleicos de Péptidos/química , Rastreo Diferencial de Calorimetría , Dimetilformamida/química , Fluorescencia , Conformación de Ácido Nucleico , Hibridación de Ácido Nucleico , Ácidos Nucleicos de Péptidos/genética , Solventes/química , Temperatura de Transición , Agua/químicaRESUMEN
The need for efficient, tailor-made catalysts has inspired chemists to design synthetic macromolecular architectures for selective catalysis. To this purpose, herein the synthesis and in-depth characterization of Ag(I)-crosslinked single-chain nanoparticles (SCNPs) is reported and their application as catalysts is demonstrated. Specifically, a copolymer of styrenic benzimidazolium chloride is synthesized as a linear precursor via reversible addition-fragmentation chain-transfer polymerization. Metalation of the benzimidazolium moieties by Ag(I) resulted in the intramolecular cross-linking of single chains via the formation of silver-N-heterocyclic carbene (Ag-NHC) linkages under dilute conditions. The successful formation of well-defined, robust SCNPs is evidenced by size-exclusion chromatography, dynamic light scattering, nuclear magnetic resonance spectroscopy, and transmission electron microscopy. Finally, it is demonstrated that the Ag-SCNPs can be used as NHC pre-catalysts, by first indirectly evidencing the formation of the corresponding unfolded NHC-CS2 polybetaine and then organocatalysing a benzoin condensation reaction.
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Compuestos Heterocíclicos/química , Metano/análogos & derivados , Nanopartículas/química , Temperatura , Catálisis , Reactivos de Enlaces Cruzados/química , Metano/química , Estructura Molecular , Plata/químicaRESUMEN
The preparation of a functional fluorine-containing block copolymer using reversible addition-fragmentation chain-transfer dispersion polymerization in DMSO as a "platform/scaffold" is explored. The nanostructures, comprised of poly(ethyleneglycol)-b-poly(pentafluorophenyl methacrylate) or PEG-b-P(PFMA), are formulated via photo-initiated polymerization-induced self-assembly (PISA) followed by post-polymerization modification using different primary amines. A combination of light scattering and microscopy techniques are used to characterize the resulting morphologies. It is found that upon varying the degree of polymerization of the core-forming block of PFMA, only uniform spheres (with textured surfaces) are obtained. These nanostructures are subsequently modified by cross-linking using a non-responsive and a redox-responsive diamine, thus imparting stability to the particles in water. In response to intracellular glutathione (GSH) concentration, destabilization of the micelles occurs as evidenced by dynamic light scattering. The well-defined size, inherent reactivity of the nanoparticles toward nucleophiles, and GSH-responsiveness of the nanospheres make them ideal scaffolds for drug delivery to intracellular compartments with reductive environments.
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Técnicas de Química Sintética/métodos , Luz , Metacrilatos/química , Nanoestructuras/química , Polimerizacion/efectos de la radiación , Polímeros/química , Aminas/química , Glutatión/química , Microscopía Electrónica de Transmisión , Modelos Químicos , Estructura Molecular , Nanoestructuras/ultraestructura , Polímeros/síntesis química , Agua/químicaRESUMEN
Precise control over reactivity and molecular structure is a fundamental goal of the chemical sciences. Billions of years of evolution by natural selection have resulted in chemical systems capable of information storage, self-replication, catalysis, capture and production of light, and even cognition. In all these cases, control over molecular structure is required to achieve a particular function: without structural control, function may be impaired, unpredictable, or impossible. The search for molecules with a desired function is often achieved by synthesizing a combinatorial library, which contains many or all possible combinations of a set of chemical building blocks (BBs), and then screening this library to identify "successful" structures. The largest libraries made by conventional synthesis are currently of the order of 108 distinct molecules. To put this in context, there are 1013 ways of arranging the 21 proteinogenic amino acids in chains up to 10 units long. Given that we know that a number of these compounds have potent biological activity, it would be highly desirable to be able to search them all to identify leads for new drug molecules. Large libraries of oligonucleotides can be synthesized combinatorially and translated into peptides using systems based on biological replication such as mRNA display, with selected molecules identified by DNA sequencing; but these methods are limited to BBs that are compatible with cellular machinery. In order to search the vast tracts of chemical space beyond nucleic acids and natural peptides, an alternative approach is required. DNA-templated synthesis (DTS) could enable us to meet this challenge. DTS controls chemical product formation by using the specificity of DNA hybridization to bring selected reactants into close proximity, and is capable of the programmed synthesis of many distinct products in the same reaction vessel. By making use of dynamic, programmable DNA processes, it is possible to engineer a system that can translate instructions coded as a sequence of DNA bases into a chemical structure-a process analogous to the action of the ribosome in living organisms but with the potential to create a much more chemically diverse set of products. It is also possible to ensure that each product molecule is tagged with its identifying DNA sequence. Compound libraries synthesized in this way can be exposed to selection against suitable targets, enriching successful molecules. The encoding DNA can then be amplified using the polymerase chain reaction and decoded by DNA sequencing. More importantly, the DNA instruction sequences can be mutated and reused during multiple rounds of amplification, translation, and selection. In other words, DTS could be used as the foundation for a system of synthetic molecular evolution, which could allow us to efficiently search a vast chemical space. This has huge potential to revolutionize materials discovery-imagine being able to evolve molecules for light harvesting, or catalysts for CO2 fixation. The field of DTS has developed to the point where a wide variety of reactions can be performed on a DNA template. Complex architectures and autonomous "DNA robots" have been implemented for the controlled assembly of BBs, and these mechanisms have in turn enabled the one-pot synthesis of large combinatorial libraries. Indeed, DTS libraries are being exploited by pharmaceutical companies and have already found their way into drug lead discovery programs. This Account explores the processes involved in DTS and highlights the challenges that remain in creating a general system for molecular discovery by evolution.