Soft Matter

Plant-derived extracellular vesicles (PDEVs) have emerged as superior candidates for oral drug delivery, exhibiting a gastrointestinal survivability that significantly exceeds that of mammalian exosomes or synthetic liposomes. However, the biophysical rules governing how plant genomic regulation translates into this exceptional mechanical resilience remain unknown. Here, we present a predictive multiscale model of plant-derived extracellular vesicles, linking a parameterised genetic state space to emergent mesoscale mechanics via supra-molecular coarse-grained molecular dynamics (SCG-MD). We demonstrate that the upregulation of sterol methyltransferases (SMT) during the plants theoretical Defence state drives the formation of a phase-separated composite architecture, where rigid domains occupying approximately 36% of the membrane surface area effectively arrest crack propagation. This state achieves a critical rupture tension of 367.0 {+/-} 0.7 mN m-1 corresponding to a 39% increase over the wild-type Ripening state. Crucially, we find that chemical composition alone is insufficient for this reinforcement; vesicles with actively sorted lipid domains (Seeded topology) outperform randomised mixtures (Spontaneous topology) by 23% at identical concentrations. Furthermore, while fluid vesicles stiffen reactively under gastric acid shock (pH 2.5) due to the steric jamming of thermodynamically neutralised headgroups, the Defence state exhibits mechanical homeostasis. These findings suggest that PDEVs function as genetically tunable composite materials, offering a design blueprint for next-generation bio-inspired drug delivery vectors. Ultimately, these theoretical indices provide a predictive biophysical framework awaiting empirical confirmation via in vitro nanomechanical assays.

We probe the structural and rheological properties of ionically crosslinked alginate, a model biopolymer hydrogel, using microscopy, rheology and viscosity dependent molecular probes. This combination of techniques enables the quantification and correlation of microstructure, microviscosity, bulk viscoelasticity and yielding dynamics. By adjusting the stoichiometric ratio, R, between the alginate biopolymer and its cation crosslinks, we observe a transition from a homogeneous network-like structure to a coarse bundle-like structure at high (R>0.67) stoichiometric ratio. Intriguingly, these bundle-like structures have distinct and counter-intuitive rheological properties. Using molecular probes, we observe a continuous decrease in microviscosity that is correlated with a decrease in bulk elastic modulus and an increase in energy dissipation. This is accompanied by a transition in the hydrogel yielding under strain from a sharp, well-defined yield point to a continuous ductile-like yielding. We ascribe these surprising transitions to the looser intermolecular interaction between alginate biopolymers in the bundle-like state, as previously predicted by x-ray scattering experiments. These findings reveal new and counter-intuitive structure-property relations that demonstrate high crosslink concentration does not necessarily translate to optimal mechanical performance. SignificanceAlginate is a polysaccharide biopolymer naturally found in brown seaweed cell walls. Extracted alginate forms ionically crosslinked hydrogels that are strong, flexible and increasingly valuable in the biomedical, packaging and food industries. A large part of the utility of these hydrogels stems from the ease with which their mechanics can be tuned through adjusting the stoichiometry between alginate and its ionic crosslinks. However, little is known about how the material properties of alginate hydrogels, in particular their rheology and dynamics, are affected by microscale structural transitions at high stoichiometric ratios. Here, we use a multi-modal approach to describe and correlate hydrogel material properties and to demonstrate that increased polymer crosslinking can, counterintuitively, sometimes weaken hydrogel performance.

Mechanical properties of biological tissues, driven by passive and active forces, play a vital role in several processes ranging from development to cancer metastasis. However, the dynamical responses of cells in tissues, subject to mechanical deformations such as shear and the associated rheological properties, are not well characterized. Here, we use three-dimensional agent-based models for normal and cancer tissues to investigate their responses to simple shear as a function of cell stiffness and stochastic active forces. In the normal epithelium, with uniform strength of active force, the yield stress as a function of shear rate follows the Herschel-Bulkley form over a range of cell volume fraction. Strikingly, the shear rate dependence and the elasticity-dependent changes in the yield stress fall on master curves upon suitable scaling. To model cancer-like behavior, a certain fraction (Np) of cells was chosen to have enhanced activity and decreased stiffness. As Np increases, the extent of collective cell movement decreases, transitioning from affine (collective) to non-affine (individualistic) movement, a finding that is in accord with imaging experiments. Simulations of a model of a stiff solid tumor, with radius Rs embedded in normal tissue, show that as Rs increases, the yield stress increases. Interestingly, the cells migrate collectively as Rs increases. A Gaussian Mixture Model (GMM) and a mean field theory quantitatively account for the simulation as well as experimental results on cancerous, non-cancerous, and a mixture of these two types. The combined theoretical and experimental study establishes that heterogeneity in stiffness and activity determines non-affine movements in normal and cancer tissues.

An e-GLUE is a polymer network containing interpenetrating polycations, which can bond the anionic network of mucosa through interfacial polycation bridging under an electric field. Such an electroadhesion involves electrophoresis of polycations, ionic complexation between polycations and the anionic network, and polycation-network entanglement, yet their quantitative understanding is lacking. Here, we formulate a theoretical model to describe electroadhesion of polymer networks by polycation interfacial bridging. We use a diffusion-drift model coupled with a Bell-like field-dependent chain friction to describe the sticky electrophoresis of polycations in an anionic sea. The formation of ionic bonds is determined by local availability of cations and anions over the penetration depth. To debond, a force must either pull polycations out from the e-GLUE network or first dissociate them from ionic complexes and then pull out from the anionic network. We model chain pullout from the bulk networks to the interface as a viscous drag against water. The adhesion strength is calculated by summing the debonding force for each polycation per unit area across all chains. Our model quantitatively links electric field strength, applied duration, polycation chain length, and cation concentration to polycation electrophoresis kinetics, ionic bond formation, and adhesion strength. We further conduct electroadhesion tests, and our model predicts well with the experimental data. Lastly, we discuss the use of the model to guide the e-GLUE design. TOC graphic O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=90 SRC="FIGDIR/small/730541v1_ufig1.gif" ALT="Figure 1"> View larger version (45K): org.highwire.dtl.DTLVardef@16524c6org.highwire.dtl.DTLVardef@15163aeorg.highwire.dtl.DTLVardef@673949org.highwire.dtl.DTLVardef@e207a0_HPS_FORMAT_FIGEXP M_FIG C_FIG For Table of Contents use only

Vesicle internalization proceeds through a series of multivesicular topologies essential for endocytic transport and cellular compartmentalization. The energetic landscapes of related transitions, including vesicle budding and pearling, are known to be governed by the coupling of spontaneous curvature, leaflet area asymmetry, and reduced volume. However, the physical principles driving the structural transformation of hemifused intermediates remain unresolved. Using a continuum elastic model, we identify a morphological phase transition in hemifused invaginating vesicles, from an initial lens-like geometry to an elongated "kettle" geometry. This transition is discontinuous as long as the invaginating vesicles reduced volume is below a critical threshold, but continuous otherwise. The kettle-like morphology is metastable across a broad range of leaflet area asymmetries, potentially enabling a hysteretic externalization pathway. Increasing either the spontaneous curvature of the shared outer leaflet or the size of the invaginating vesicle, alone or in tandem with the host vesicle, turns the kettle morphology into the global free energy minimum. Notably, simply scaling up the size of both vesicles does not eliminate the free energy barrier. This quantitative characterization provides a structural reference for identifying internalization intermediates witnessed in experimental imaging, and maps the morphological evolution of the internalization pathway across its physical parameter space.

Wound repair is an important mechanism to preserve tissue integrity in organisms after injury. However, why different tissues exhibit different mechanisms to repair wounds is a long-standing question that remains unanswered. In this work, we theoretically explore the role of the purse string, an actomyosin contractile cable used by tissues to close small wounds. Does the tissue 3D geometry influence the efficiency of the purse string in driving wound closure? Using a 3D biophysical model, we study in silico tissues with the same cell volumes but different aspect ratios, ranging from squamous to thick and tall tissues. The model predicts that taller cells are easily deformed by the purse string. In contrast, very squamous cells require a very strong purse string that might demand additional cellular mechanisms to close the gap. These findings establish a theoretical framework to predict the optimal biophysical mechanisms of wound healing in different tissues. Graphical abstractCells of different aspect ratios can be observed in a range of organisms with different function and mechanics. The wound healing efficiency of the purse string increases with the cell aspect ratio in our theoretical exploration. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=135 SRC="FIGDIR/small/743165v1_ufig1.gif" ALT="Figure 1"> View larger version (23K): org.highwire.dtl.DTLVardef@d44ab0org.highwire.dtl.DTLVardef@1737cbaorg.highwire.dtl.DTLVardef@101b5d4org.highwire.dtl.DTLVardef@1487f26_HPS_FORMAT_FIGEXP M_FIG C_FIG

Recent experiments show that protein condensates sitting on opposite surfaces of a flat lipid membrane move together and prefer to overlap, even though they cannot touch each other. This points to an indirect, membrane-mediated interaction. Two mechanisms could be responsible: a curvature-induced interaction, which is energetic in origin, and a fluctuation-induced interaction, which is entropic. Here we study both with coarse-grained molecular dynamics simulations, using Cookes implicit-solvent lipid model together with a generic bead-spring polymer model for the condensate. We compute the potential of mean force between two condensates across the membrane. For condensates of the same size, full overlap is unfavorable, and the pair instead settles into a partially overlapping state that bends the membrane into an S-like shape. When the two condensates differ strongly in size, full overlap becomes favorable. We explain this with a simple geometric picture. The condensate wets the membrane as a thin film and imposes curvature only along its rim, while membrane tension flattens the membrane under its interior. The resulting ring of curvature can trap a smaller condensate on the opposite side. We also compare the bending undulations and the effective bending modulus of a bare membrane, a membrane with one condensate, and a membrane with condensates on both sides. A wetting condensate suppresses the undulation modes and stiffens the membrane, but whether this makes overlap entropically favorable remains inconclusive. Our results indicate that the coupling is driven mainly by curvature, and that it depends on the wetting mechanism and on the membrane tension.

Lipid droplets (LDs) are cellular organelles responsible for lipid storage and metabolism. The mechanism of biogenesis of LDs involves phase separation of neutral lipids from the surrounding phospholipids, which generates oil lenses embedded in lipid bilayers, also known as nascent LDs. As nascent LDs grow, at some point they bud out of the bilayer, forming nearly spherical droplets. Nascent LDs have different propensity to bud, and it has been proposed that their shape provides information on such propensity; however, LD shape is difficult to determine experimentally. Here we studied the shape of lipid droplets using MD simulations at the coarse-grained level, and compared it to the predictions by an established theory. Our general system setup features an oil lens embedded into a flat, periodic bilayer. We found that the shape of simulated nascent LDs resembles a spherical cap (i.e., it has constant curvature over most of the surface), in excellent agreement with the theory, already for very small droplet sizes. The aspect ratio (height/radius) of nascent LDs increases with increasing LD volume, increasing membrane softness, and increasing surface tension between oil and water, also in agreement with theoretical predictions; however, it remains lower than 1 (i.e., the ratio for a sphere) for LDs of up to 40 nm in diameter. Fitting the simulated LD shapes with a theoretical shape equation suggests that a non-zero surface tension is present in both the monolayer and in the bilayer region. The existence of a relatively high surface tension in the bilayer region is confirmed by local stress calculations, and indicates that the periodic system setup does not reproduce the properties of nascent LDs in the endoplasmic reticulum, where the bilayer tension is two orders of magnitude lower. However, the simulations provide a microscopic view into the properties of droplet embedded vesicles.

Poly-L-Lysine (PLL) mediates the non-specific adhesion of cells and is commonly used in Atomic Force Microscopy (AFM) measurements, to ensure that cells remain attached to the substrate. However, it is acknowledged that adhesion affects the measured mechanical properties, in particular in the case Red Blood Cells (RBCs). This results in a wide range of Youngs modulus E reported in the literature. The present study aims at providing a systematic approach to the impact of non-specific adhesion on the rheology of RBCs. It provides a correlation between the topography profile of adherent RBCs and their rheology, from weak (cPLL = 10-3 mg/mL) to strong-adhesion (cPLL = 100 mg/mL) regimes. Using RICM and AFM, we find that there is a continuum of RBC shapes promoted by adhesion, from concave to dome-shaped, as predicted by the theory of vesicle adhesion. Their elastic properties discriminate them into two populations depending on adhesion strength, where stiffer RBCs (E {gtrsim} 100 Pa) correlate with dome-shaped cells. These findings are supported by rheology measurements of the dynamic complex shear modulus G*(f): while the storage modulus increases with cell-substrate adhesion, reflective of an increased membrane shear modulus, the loss modulus remains unchanged. Finally, further analysis inspired by membrane theory shows that different deformation modes may be triggered during indentation of either weakly or strongly adhering RBCs, illustrating the limits of the Hertz model.

Inefficient endosomal escape is a crucial barrier to intracellular delivery of nucleic acid therapeutics using lipid nanoparticles (LNPs). The use of ionizable lipids (ILs) has significantly improved cargo delivery efficiency, yet the physical basis of their interaction with endosomal membranes and their role in endosomal escape remain unclear. It has been suggested that, as ILs become cationic during endosomal acidification, electrostatic affinity promotes fusion of the LNPs with the endosome. In this paper, we propose an additional mechanism in which ILs are redistributed from LNPs to host membranes, modulating the elastic properties and curvature of the membrane, lowering the energetic threshold for endosome disruption. To test this, we quantified the spontaneous curvature of clinically relevant ILs and ATP-binding lipids and measured the membrane mechanics of giant unilamellar vesicles (GUVs) with an endosome-relevant composition at endosome-relevant pH. Small-angle X-ray scattering (SAXS) measurements reveal that the incorporation of ILs and ATP lipids into endosome-mimetic membranes shifts the spontaneous curvature towards more negative values. Micropipette aspiration experiments indicated a decrease in the apparent area compressibility modulus of membranes doped with ILs and ATP lipids. In addition, membranes showed enhanced fluctuation amplitudes and altered relaxation behavior, consistent with membrane perturbations associated with lipid insertion and pH- or ATP-driven destabilization. Under conditions promoting the partitioning of ILs or ATP-binding lipids, we further observed reduced bending rigidity and increased heterogeneity in membrane tension. Together, these results support a model in which ILs (as well as newly developed ATP-binding lipids) partition into endosomal membranes, softening the membrane and generating local curvature frustration that facilitates endosomal disruption during the natural acidification process. By quantitatively linking lipid composition with changes in membrane elasticity and fluctuation dynamics, this work provides a biophysical framework for understanding how lipid redistribution may contribute to endosomal escape and improve delivery efficiency.

Small molecules regulate biomolecular condensates in a biphasic manner, promoting liquid-liquid phase separation (LLPS) at low concentrations while suppressing it at higher concentrations. Despite increasing experimental evidence for such re-entrant behavior, a unified physical description remains lacking. Here, we identify a minimal thermodynamic mechanism for re-entrant LLPS by coupling Cahn-Hilliard dynamics to a concentration-dependent Flory interaction parameter containing competing LLPS-promoting and inhibitory contributions. The resulting model reproduces experimentally observed nonmonotonic condensate formation in Tau-tannic acid and TDP-43-bis-ANS systems, including the concentration-dependent emergence and dissolution of protein-rich domains. Spinodal analysis reveals finite concentration windows for phase instability and demonstrates that re-entrant mixing is encoded directly in the free-energy landscape. The framework further captures morphology transitions and diffusive coarsening within the phase-separated regime. These results establish a general mesoscale description of chemically regulated condensates and provide design principles for controlling phase separation through small-molecule modulators.

The cytoskeleton determines cell shape, mechanical properties, and motility by interconnected networks of protein filaments - actin filaments, microtubules and intermediate filaments. Their collective function relies on crosstalk between these filament systems, yet the physical basis of interactions between the filaments remains insufficiently understood. Actin and vimentin filaments and networks frequently co-localize within cells and jointly regulate contractility, force transmission and mechanical resilience, indicating functional cooperation. However, it remains unclear whether these interactions arise from direct filament-filament interactions or are mediated exclusively by accessory crosslinking proteins. Studies of reconstituted composite networks probing direct interactions by rheology have yielded inconsistent results. Here, we show that single actin filaments and vimentin intermediate filaments do indeed interact directly, forming force-bearing contacts in the absence of crosslinking proteins, with interaction strengths comparable to other previously reported cytoskeletal filament pairs. Using quadruple optical tweezers combined with microfluidics and confocal microscopy, we systematically probe these interactions under controlled conditions across a range of ionic environments. We find that, in contrast to other filament pairs, variations in ionic strength do not appreciably affect the interaction breaking forces between actin and vimentin filaments. However, the interaction geometry determines the achievable interaction strengths, because the limited stretchability of the actin filaments sets an upper bound to the measurable force range. This limit also imposes a restriction on direct quantification of interaction parameters, which we circumvent by a Bayesian unmasking strategy that allows us to infer bond parameters despite the breaking of actin filaments. Furthermore, actin bundling enhances the stability against breaking, enabling the detection of higher interaction forces. These findings demonstrate that actin and vimentin form a mechanically interacting system through direct filament bonds, and our work establishes a minimal, protein-linker-independent physical basis for actin-vimentin crosstalk and quantifies the interaction forces between the two filament types.

Cell monolayers are active, orientationally ordered materials whose mechanics can depart from near-equilibrium behavior. Existing continuum theories often inherit assumptions from equilibrium liquid-crystal physics, motivating explicit nonequilibrium formulations. Here, we develop a minimal continuum model of two-dimensional monolayers based on odd mechanics, accounting for broken symmetries and nonequilibrium dynamics. We show that nematic order can support an odd viscous modulus generated by broken time-reversal symmetry and spatial anisotropy, without chirality. The model reproduces half-integer defect motion and stress profiles in Madin-Darby canine kidney (MDCK) monolayers, as well as defect-associated cell accumulation and depletion in neural progenitor and ovarian mesothelium systems. Finally, we estimate the viscous-moduli tensor from measured stress, velocity, and orientation fields in MDCK monolayers and identify a nonzero odd modulus. Our results show that odd mechanics provides a minimal framework for nonequilibrium cell monolayers, complementing conventional active-nematic theories.

We present a comparative study of the inner membrane of three Gram-positive bacterial strains, namely S. aureus, S. epidermidis and N. lacusekhoensis. A lipidomics study is used to obtain the lipid architecture and composition for S. epidermidis found in the skin microbiome and N. lacusekhoensis, an extremophile present in halophilic and alkophilic environments. Differences between the strains arise from both the lipid architecture and the cardiolipin content varying from 5% in S. aureus to 85% in N. lacusekhoensis. We develop coarse grained (CG) Martini-3 membrane models which reproduce structural properties such as membrane area, thickness, density distributions as well as ion-correlations with all-atom models. Inter-lipid correlations reveal a homogeneous distribution of lipids in the membranes despite the wide variation in lipid types and composition. Mechanical properties such as the area stretch modulus increased with cardiolipin content, however the bending modulus has a more complex dependence on membrane charge and lipid type. Using the CG models we evaluate the insertion free energies for four widely used antimicrobial molecules. Entry barriers for thymol and methylparaben arise from the charge density modulation at the membrane headgroups due to counterion condensation. The entry mechanisms of the antimicrobial peptide cecropin-melittin-15 (CM15) and the preservative molecule ethyl-lauroyl-arginate (ELAR) are found to be similar across all three strains. We also illustrate the manner in which the extremophilic strain, N. lacusekhoensis with its high cardiolipin content, modulates the partitioning kinetics of the antimicrobial molecule thymol with pH and salt. Our study reveals that membrane properties are largely conserved across the three model membranes. The molecular models and insights emerging from the present work should aid in the development of novel antimicrobials against Gram-positive strains.

Antimicrobial peptides (AMPs) act at the membrane interface, where they remodel lipid packing defects and redistribute lateral stresses, yet a quantitative, dose-dependent understanding of how they alter membrane mechanical properties remains incomplete. We use coarse-grained MARTINI 3 molecular dynamics simulations to systematically characterize the mechanical and microstructural response of a 70:30 POPE:POPG bilayer to three AMPs spanning distinct structural classes: aedesin (alpha-helical, 2MMM), arenicin-1 (beta-hairpin, 2JSB), and indolicidin (disordered, 1G89). For each peptide we vary the surface loading from one to four peptides per leaflet and extract the bending modulus Kc, the area compressibility modulus KA, peptide localization depth, bilayer thickness, peptide-lipid and peptide-peptide spatial organization, and leaflet-resolved lipid packing defect distributions. All three peptides soften Kc monotonically with loading, but at per-peptide rates that span a threefold range and order systematically by structural class: - 1.39 {+/-} 0.09, - 0.66 {+/-} 0.04, and - 0.44 {+/-} 0.01 kBT per peptide for aedesin, arenicin-1, and indolicidin, respectively. The tilt and twist moduli remain invariant across all conditions, indicating that the perturbation operates selectively on long-wavelength collective deformation modes. KA softens for the two structured peptides but is statistically indistinguishable from the control for indolicidin, a dissociation we trace to a supraphosphate adsorption versus interfacial insertion dichotomy: structured peptides sit above the phosphate plane and act as supraphosphate wedges, while the disordered peptide threads into the interface without coherently displacing lipids. Independent geometric, spatial-organization, and microstructural observables corroborate this framework, with the deep versus shallow defect remodeling asymmetry providing a clean microstructural counterpart to the Kc-KA dichotomy. Acyl chain order parameters resolve the per-lipid splay from the bilayer-averaged response and show that the per-lipid perturbation tracks conformational state rather than peptide length: the two structured peptides impose comparable per-lipid chain disordering despite differing in length, while the disordered peptide imposes far less. These findings establish a quantitative connection between peptide-induced defect remodeling and the elastic response of the bilayer, and suggest a design principle in which conformational restriction maximizes the per-peptide membrane perturbation, motivating experimental tests on stapled-peptide AMP analogs.

Fingertip friction plays a central role in tactile exploration and object manipulation. During sliding, tangential force depends jointly on the real contact area and the interfacial shear stress, both of which can be influenced by sliding conditions. However, changes in fingertip friction are often interpreted primarily through changes in real contact area, whereas the accompanying changes in interfacial shear stress remain less well characterized. This gap is especially relevant for electrostatic surface haptic displays, which modulate fingertip friction by applying a voltage between the finger and the touch surface. Here, we experimentally quantify the mean interfacial shear stress of a sliding fingertip on an electrostatically actuated touchscreen using simultaneous measurements of tangential force and optically resolved real contact area. Ten participants performed sliding trials across three speeds and three normal forces with and without electrostatic actuation. Interfacial shear stress increased with speed and decreased with normal force; in both cases, these trends arose because real contact area varied more strongly than tangential force. Electrostatic actuation further reduced interfacial shear stress, as increasing voltage produced a larger increase in real contact area than in tangential force. These findings show that interfacial shear stress varies systematically with sliding conditions and electrostatic actuation, clarifying how changes in real contact area and interfacial shear stress combine to shape fingertip-surface friction.

Budding is a fundamental membrane-remodeling process central to many cellular functions and is exploited by numerous enveloped viruses to acquire their lipid envelopes. Despite extensive molecular characterization, the physical mechanisms that determine whether budding proceeds to completion or becomes stalled remain unclear. Here, we develop a theoretical model based on the Helfrich elastic formalism to investigate how membrane geometry and boundary conditions regulate the elastic energy of viral budding. We analyze two representative cases: budding from a flat membrane, characteristic of HIV-1 and alphaviruses, and budding from a vesicle, as observed for SARS-CoV-2 in the ER-Golgi intermediate compartment (ERGIC). Our results reveal distinct energetic pathways: vesicle-like geometries exhibit a stronger energetic bias toward closure, whereas flat membranes develop extended low-slope regions in the energy landscape that can hinder completion. Relaxing far-field boundary constraints reduces the energetic cost associated with membrane area conservation and renders the flat-membrane case energetically comparable to the vesicle case, providing a physical explanation for why viruses frequently bud adjacent to one another or within pre-curved membrane regions. Comparison with thin-section TEM images of alphavirus budding shows results consistent with the theoretical membrane profiles. Together, these findings establish how curvature coupling, boundary flexibility, and local membrane geometry cooperate to control the efficiency and completion of membrane budding.

Hydrated extracellular polymeric phases (such as mucus, biofilms, and extracellular matrices) have traditionally been viewed as passive barriers. We complement and extend this view by analysing these systems through the murburn framework and liquid-liquid phase separation (LLPS) biophysics. Using quantitative modeling, we first demonstrate how frothy mucus in amphibian egg-masses enhances oxygen delivery while buffering diffusible reactive species (DRS), leading to improved developmental synchrony. We then model the human cervical mucus system, showing its cycle-dependent transitions between coherent barriers (pregnancy), active transduction media (ovulation), and controlled inflammatory remodeling (labor). Finally, we present thiolated polyglycerol sulfate (dPGS-SH) as a synthetic validation (another groups recently published work): this rationally designed mucolytic agent recapitulates native mucuss DRS-modulating properties and shows superior efficacy for addressing cystic fibrosis pathology. With such pan-systemic perspectives, we argue that phase-separated hydrated polymeric matrices represent one of evolutions most conserved solutions for regulating stochastic murburn chemistry, enabling organisms to exploit oxygen while preserving biological coherence. From biofilms to birth, this framework unifies the physicochemical basis of lifes most fundamental processes.

Keratin proteins are fundamental structural components of hair fibers, contributing to their mechanical resilience, elasticity, and fracture resistance. However, systematic molecular-scale characterization of keratin unfolding mechanics across protein types remains limited, restricting the connection between protein-level deformation mechanisms and hierarchical hair fiber mechanics. Here, we establish a comparative molecular-dynamics-based framework for characterizing the unfolding behavior and nanomechanical response of a curated dataset of 51 keratin proteins. We conduct implicit atomistic molecular dynamics (MD) simulations, including equilibration and steered molecular dynamics (SMD) under four accelerated pulling velocities, to quantify unfolding forces, energy absorption, and structure-property relationships. These accelerated pulling conditions are interpreted as computational probes of relative molecular-scale trends, rather than direct reproductions of experimental hair-fiber strain-rate regimes. Across these accelerated SMD conditions, the simulations show rate-sensitive increases in unfolding force and energy absorption, consistent with constrained molecular relaxation during faster molecular pulling. Stronger correlations between nanomechanical properties and molecular descriptors emerge at higher pulling rates, and the nanomechanical responses of different keratin types (Type I and II) are also compared. The findings provide molecular-level insights into protein unfolding mechanisms that may contribute to the mechanical behavior of hierarchical keratin structures. This study establishes a quantitative framework for comparative keratin unfolding mechanics, providing molecular-level descriptors for future multiscale modeling of hair fiber behavior. These results support applications in biomaterial design, hair fiber durability analysis, and bioinspired material engineering. Future work will integrate these nanomechanical descriptors with fiber-level mechanics and machine learning-based keratin design.

Chronic wounds (principally pressure sores, venous leg ulcers and diabetic foot ulcers) are a drain on global health services and remain a major area of unmet clinical need. Chronic wounds are characterised by a bacterial biofilm (densely aggregated colonies of bacteria encased by a matrix of extracellular polymeric substances), which hinders innate immune response and can prevent wound healing. Bioactive glass (BG) fibres doped with antimicrobial metal ions, such as silver, can offer a promising treatment for chronic wound infections, where silver is well known for its antimicrobial activity against a range of pathogens and is commonly used in wound dressings. We first present a system of non-linear partial differential equations to model the treatment of a chronic wound biofilm infection with BG fibres. The BG fibres are assumed to have two mechanisms of action against the biofilm: physical disruption of the top layers of the biofilm by the BG fibres; and release of antimicrobial silver ions from the BG fibres, which then diffuse into the biofilm and can kill the bacteria. Treatment-associated parameters are estimated from in vitro experimental data using a combination of least-squares minimisation and Approximate Bayesian Computation (ABC). Sensitivity investigations are performed on other parameters that cannot currently be calculated experimentally to investigate their influence on treatment efficacy. We thus predict key parameter regimes that should lead to biofilm eradication, crucially informing the future design of metal-doped BG fibres to maximise treatment efficacy. Author summaryChronic wounds are a huge drain on global health services and will become even more problematic due to an ageing population. Current treatment methods are often unsuccessful, where treatment failure is exacerbated by the presence of a biofilm infection. Biofilms consist of communities of bacteria that adhere to the wound surface and produce extracellular polymeric substances, which can protect the bacteria by acting as both a physical and chemical barrier. More recently, there has been a focus on biofilm-based wound care, where the aim is to firstly eradicate the biofilm infection, which then enables wound healing to occur naturally. Our aim is to produce a novel treatment that can target and eradicate the biofilm infection, followed by directly assisting the wound healing. Bioactive glass (BG) fibres doped with silver offer a promising treatment as they have both anti-biofilm effects and can also stimulate the wound healing process. Here, we restrict attention to their anti-biofilm properties. By developing a mathematical model, we can predict treatment outcomes under several different scenarios, the results of which can then be utilised during design of the BG fibres. Using this combination of computational and experimental approaches, we reduce both the cost and time of optimising this promising treatment.