David Yuen Wah Ng

Many tumours release lactate as a major metabolic product and signalling molecule. Here we use lactate flux as an endogenous trigger for covalent hydrogel formation. Phenol-functionalised alginate remains soluble until cell-derived lactate is oxidised by lactate oxidase; the generated hydrogen peroxide is used by horseradish peroxidase to crosslink phenols and form a matrix at metabolically active sites. Hydrogels form within minutes and reach storage moduli from approximately 10 Pa to 5 kPa. In tumour-spheroid models, including a patient-derived glioblastoma spheroid model, local lactate production generates spatially confined gelation that extended up to around 1 mm from the spheroid surface. Nanoindentation and fluorescence correlation spectroscopy reveal radial stiffness and polymer-density gradients, while proteome profiling and imaging indicate reduced proliferative signalling and increased markers associated with migration and matrix remodelling. These findings establish metabolite-gated hydrogelation as a strategy to couple cellular metabolism to covalent matrix assembly, mechanics and transport, providing a bio-synthetic platform for modelling cell–matrix reciprocity and tumour confinement.

Programming three-dimensional order in peptide-based materials requires lateral interactions that are precise enough to propagate over hundreds of nanometres, yet robust enough to operate in water. Here, we show that a rationally designed coiled-coil peptide meets both demands by assembling into a hierarchical suprahelix that promotes spontaneous crystallisation under physiological buffer conditions. Coiled-coil dimers wind around one another to generate the higher-order suprahelix. Subtle lysine-to-arginine substitutions tune lateral cohesion, revealing a non-monotonic dependence on arginine density: 46-residue peptides with three or six arginine residues form ellipsoidal nanocrystals, whereas arginine-free or arginine-rich variants form amorphous aggregates. Time-resolved spectroscopy and cryogenic electron microscopy show that crystallisation proceeds by a non-classical pathway, in which condensed protofibrils align before consolidating into an ordered lattice. Cryo-electron tomography supports the single-domain nature of the resulting nanocrystals, and three-dimensional electron diffraction shows that both crystalline variants adopt the same near hexagonal unit-cell metrics. These findings translate a principle from protein crystallography, that arginine favours crystal contacts relative to lysine, into a sequence-level design parameter for coiled-coil nanocrystallization, providing a route to programmable three-dimensional order in soft molecular materials.

Cells have evolved to defend against perturbations by maintaining their intrinsic homeostasis to survive. However, no intrinsic pathway exists for them to expel new-to-biology synthetic nanostructures. Here we establish crosstalk between supramolecular transformations and genetic responses, achieving programmable influx–efflux cycles of nanoassemblies in living bacterial cells to restore redox and energy homeostasis. Specifically, a model photosensitizer–peptide conjugate undergoes multiple redox cycles between methionine and methionine sulfoxide (MetO), resulting in reversible morphological transformations between nanofibers (NFs) and nanoparticles (NPs). Upon irradiation, the oxidized peptide NPs are internalized into bacteria. To counteract the perturbations caused by internalized NPs, engineered bacteria activate the expression of MetO reductases in response to photo-oxidative stress. The internalized NPs are intracellularly enzymatically reduced such that they are expelled as reduced NFs, setting the stage for subsequent cycles. The concept presented here paves the way for the interlinked network between dynamic supramolecular assemblies and cellular regulatory behaviors.

Self-assembling peptides are versatile building blocks for biomaterials owing to their programmable sequences and ability to form complex supramolecular architectures. Designing systems that operate dynamically at the biological interface is particularly compelling, as living systems rely on both stimulus responsiveness and continuous energy dissipation to regulate structure and function. However, most synthetic peptide assemblies remain confined to near-equilibrium behaviour, whereas chemically fuelled dissipative systems often lack compatibility with biological environments. In this Review, we discuss recent advances in stimulus-responsive and dissipative peptide assemblies, highlighting their distinct design principles and functional capabilities. We compare sequence-encoded and trigger-based strategies with chemically fuelled reaction networks that enable transient assembly. Finally, we outline emerging strategies to bridge these approaches, including improving bioorthogonality, tuning concentration regimes, and integrating cellular processes. Together, these concepts provide a framework for developing interactive peptide biomaterials with life-like functions.

Spacer length is a key molecular parameter governing the self-assembly of short peptides. Here, we investigate isoleucine-cysteine-alanine (ICA) tripeptides containing carbon spacers of 6, 3, or 0 methylene units linking the peptide backbone to a hydrophobic naphthalene (Nap) π-block. Using complementary spectroscopic and microscopic techniques, we show that spacer length controls the balance between conformational flexibility and directional non-covalent interactions, thereby dictating assembly pathways and material properties. The results establish a correlation between spacer length and assembly propensity, with the longest spacer (C ₆ ) consistently promoting aggregation more effectively than the intermediate analogue (C ₃ ), whereas peptides containing the rigid C ₀ -spacer fail to develop ordered nanostructures. These findings identify spacer length as a powerful design parameter for tuning peptide self-assembly across multiple length scales.

Biomolecular condensates formed through liquid-liquid phase separation play central roles in intracellular organization and regulation. Replicating such dynamic compartmentalization using minimal synthetic components remains exceptionally challenging inside living cells. Here, we report short cationic peptides that undergo directed complex coacervation in living cells through preferential interactions with endogenous polyanionic biomolecules. Although the peptides were designed to contain a mitochondrial targeting motif, the Arg residues and cellular RNA guide the supramolecular interactions toward selective enrichment of liquid-like coacervates in nucleolar regions. In vitro studies reveal that polymeric RNA mimics promote coacervation far more efficiently than ATP, establishing RNA-peptide interactions as the principal driving force. In cells, nucleolar complex coacervates form rapidly and exhibit liquid-like behavior with fast molecular exchange. Importantly, the assemblies are transient and reversible: sustained peptide supply maintains the condensed state, whereas substrate depletion triggers droplet dissolution and recovery of cellular function. These findings demonstrate that endogenous biopolymer distributions can guide and participate in the formation of synthetic coacervates with minimalistic peptides, achieving reversible reorganization of intracellular components. More broadly, this work provides a framework for engineering synthetic coacervates with nonequilibrium, life-like features that operate in direct exchange with living cellular environments.

ABSTRAKT: Natürliche Photosynthese wird durch Sonnenlicht angetrieben, wobei ein großer Teil des sichtbaren Spektrums durch die Lichtsammelkomplexe (LHCs) absorbiert wird, welche die Energie anschließend an das Reaktionszentrum weiterleiten. Inspiriert von der Natur haben wir eine Lichtsammel‐ und Energieübertragungskaskade in biomimetischen Lipid‐Doppelschichten von Liposomen aus DPPC (1,2‐Dipalmitoyl‐sn‐glycero‐3‐phosphocholin) aufgebaut, wobei wir Fluorescein, 2‐(3,6‐Dihydroxy‐9H‐xanthen‐9‐yl)‐5‐dodecanamidobenzoesäure (FlC ₁₂ ) als primären Absorber und Eosin Y, Hexadecyl‐2‐(2,4,5,7‐tetrabrom‐3,6‐dihydroxy‐9H‐xanthen‐9‐yl)benzoat (EYC ₁₆ ) als Energieakzeptor in der Membran verankert haben, um Sauerstoff zu sensibilisieren und so die reaktive Sauerstoffspezies ¹ O ₂ zu erzeugen. Diese wird als Oxidationsmittel genutzt, um das Modellsubstrat Nicotinamidadenindinukleotid (NADH) innerhalb der kompartimentierenden Liposomen‐Nanoreaktoren zu oxidieren. Es wurde beobachtet, dass unser metallfreies LHC‐System nur einen geringen Einfluss auf die Photooxidationsgeschwindigkeit von NADH hat, wenn die Nanoreaktormembran symmetrisch funktionalisiert ist. Im Gegensatz dazu führt eine asymmetrische Funktionalisierung der Membranen der Liposomen‐Nanoreaktoren zu einer Beschleunigung um 16 bis 27 %, wenn mehrfarbige Leuchtdioden (LED) bzw. simuliertes Sonnenlicht verwendet werden.

In nature, photosynthesis is driven by solar light and a large proportion of the visible spectrum is absorbed by the light harvesting complexes (LHCs), which then transfer the energy to the reaction center. Inspired by nature, we implemented a light harvesting energy transfer cascade within biomimetic lipid bilayers of liposomes built with DPPC (1,2‐dipalmitoyl‐sn‐glycero‐3‐phosphocholine), using membrane‐anchored fluorescein, 2‐(3,6‐dihydroxy‐9H‐xanthen‐9‐yl)‐5‐dodecanamidobenzoic acid (FlC ₁₂ ) as primary absorber and membrane anchored eosin Y, hexadecyl 2‐(2,4,5,7‐tetrabromo‐3,6‐dihydroxy‐9H‐xanthen‐9‐yl)benzoate (EYC ₁₆ ), as energy acceptor to sensitize oxygen and generate the reactive oxygen species ¹ O ₂ . Finally, the model substrate nicotinamide adenine dinucleotide (NADH) is oxidized by ¹ O ₂ within the compartmentalizing liposome nanoreactors. It was observed that our metal‐free LHC system has only a minor effect on the photooxidation rate of NADH when the nanoreactor membrane is functionalized symmetrically. By contrast, asymmetric membrane functionalization of the liposome nanoreactor membranes leads to acceleration by 16% to 27% when using multi‐colored light emitting diodes (LED) or simulated solar light, respectively.

We employ cationized human serum albumin as a scaffold for attaching poly(ethylene glycol) (PEG) chains at precise locations along the protein backbone. Subsequent denaturation unfolds the protein backbone, resulting in brush polymers with a well-defined, monodisperse, polypeptide backbone with PEG side chains. The defined variation of PEG chain number allows for a systematic investigation of the impact of PEGylation on the protein secondary structure, protein backbone and PEG dynamics, as well as PEG crystallization. Strikingly, PEG side chains in the polypeptide-PEG hybrids can crystallize even at low grafting density. As a result, crystallization is embedded in the hybrids, evident from the low degree of crystallinity, reduced melting temperature, and superslow spherulitic growth rates. The crystallization temperature in the hybrids approaches the homogeneous nucleation limit of PEG, only accessible via confinement (e.g., in nanopores). Our findings underscore the unique crystallization characteristics of PEG side chains in polypeptide-PEG hybrids.

Nucleic acids are fundamental to life, encoding and storing genetic information, catalyzing biological processes, and directing protein synthesis. The primary classes, DNA and RNA, have become increasingly significant in biomedical applications due to advances in stabilizing these structures against degradation and elucidating their molecular roles. Nucleic acids can be functionalized with polymers, peptides, proteins, lipids, saccharides and other functional units to yield hybrid biomaterials with tailored properties for nanomedicine and materials science. This review summarizes conjugation strategies and provides a critical overview of purification approaches, including chromatographic, membrane‐based, and electrophoretic methods, highlighting their principles, advantages, and limitations. Emphasis is placed on the relationship between synthesis route and purification choice, as well as common challenges such as solubility, aggregation, and incomplete coupling. Broadly applicable strategies for the successful synthesis and purification of nucleic acid conjugates are discussed, along with an overview of recent approaches for conjugates with polymers, peptides, proteins, lipids and saccharides. Finally, strategies are summarized for obtaining high‐purity conjugates suitable for biomedical and materials applications.