Nature Physics

Microbes across species and environments form biofilms, living materials composed of cells and extracellular polymers. Biofilm-dwelling cells benefit from emergent soft matter physics that sculpts three-dimensional morphologies and osmotically absorbs nutrients. Although biofilms are modeled as viscoelastic gels, the physical origins of the phase transition underlying their conversion from groups of cells to living gels have not been systematically investigated. Here, we show that Bacillus subtilis biofilms use polymer composition to tune their physical properties and drive gel formation. Using imaging and water immersion experiments with matrix knockout strains, we demonstrate the complementary roles of two polymers in this developmental transition: hydrophilic poly-{gamma}-glutamate swells colonies by absorbing water and exopolysaccharides serve as effective cross-linkers, causing a sol-gel-like phase transition that imparts structural integrity. With matrix knockout co-culture biofilms, we independently modulate the production of each polymer and reveal a phase space of biofilm morphologies. Colonies that produce both polymers develop macroscopic wrinkles. A thin-film model predicts biofilm wrinkling from swelling-generated internal strain coupled to elasticity. The model reproduces the shape of our observed morphological phase diagram. Our results demonstrate that bacteria leverage gelation to vary their material properties and morphologies, with implications for microbial ecology and engineering living matter.

Destructive mechanical breakdowns and fractures are ubiquitous events in driven physical matter; living tissues, by contrast, can rupture repeatedly while restoring integrity. Here we study rupture-repair interplay in regenerating Hydra tissues, which cycle through osmotic inflation, pressure release by rupture, and resealing. We utilize bright-field imaging of the tissues projected area as a readout of the rupture magnitude before it is arrested. Analyzing these event statistics, we find that the tail of the area-drop distribution is controlled by Ca2+-dependent repair efficiency. When the Ca2+ response is weakened, either by partially blocking gap-junctions mediating the intercellular communication, or by inhibiting stretch-activated Ca2+ channels, the actomyosin force that arrests the rupture process is delayed or reduced. Under these conditions, rare large pressure releases become more likely, and the tail of the distribution crosses over from an exponential behavior, exhibiting a characteristic scale, to a power-law one consistent with a critical-like regime reflecting intermittent rupture propagation. These results identify mechanically evoked Ca2+ activity as a control axis linking repair to rupture statistics in a living tissue. It supports a picture of rupture front advancing by stick-slip-like dynamics as it encounters a heterogeneous mechanical landscape, akin to failure-front propagation in disordered materials.

In living systems across developmental and cancer biology, populations of cells on surfaces organize themselves into aggregates that mediate function and disease. Recent experimental studies have identified that such aggregates can have emergent fluid-like properties such as surface tension, yet the physical origin of these properties is not clear. Here, we develop a minimal cell-based model in which cell-cell and cell-substrate interactions are governed by active intermittent attachments. We explain the transition of cells from a dilute population to a dense aggregate, and quantify the emergent material properties underpinning this transition. We use our model to interpret experiments on dewetting of aggregates of MDA-MDB-231 cancer cells and shape fluctuations of surface-associated OVCAR3 cell aggregates. Finally, we show how spatial heterogeneity in attachments governs collective chemotaxis of cell aggregates. Together, these results reveal how active intermittent attachments generate cell aggregates with emergent material properties, with broad implications for development and cancer.

Cells can experience time-varying mechanical cues, particularly when navigating through changing and complex microenvironments. Yet whether and how cells retain and use a short-term mechanical memory of recent deformations remains unclear. Here we show that, in glioblastoma cells, this memory is encoded by transient cytoskeletal anisotropy. Using uniaxial magneto-mechanical actuation aligned or perpendicular to the cell long axis, nanoindentation, and selective cytoskeletal perturbations, we find that distinct architectures of the actin cytoskeleton drive opposite mechanical responses: actin stress fibers mediate stiffening under stretch, whereas the actin cortex underlies softening under perpendicular loading. Vimentin intermediate filaments are essential to stabilize actin organization under load, preserving deformation-specific mechanics. Quantitative imaging reveals that mechanical actuation induces network-specific alignment and anisotropy, stronger for actin than vimentin, that persists transiently after unloading and bias subsequent responses, revealing a short-lived, deformation-dependent mechanical memory. To integrate these observations, we develop a multi-network constitutive model that links cytoskeletal architecture and loading history to cell-scale mechanics, reproducing both the asymmetric mechanical responses and the measured reorganization dynamics. These findings provide a structural basis for short-term mechanical memory and suggest how cancer cells could exploit residual anisotropy to adapt to fluctuating solid stresses and confinement, transiently biasing polarization, force transmission, and directional persistence during invasion. They also identify vimentin-actin coupling and the kinetics of cytoskeletal remodeling as potential levers to limit the mechanical adaptability of invasive cancer cells.

Collective migration and pulsatile flows in epithelial monolayers are commonly quantified using projected area, implicitly assuming constant cell volume and prism-like cell geometry. These "21/2D" assumptions neglect the intrinsic three-dimensional height and volume dynamics that accompany density fluctuations in confluent, space-filling tissues. Here, we combine 2D quantitative phase imaging (QPI) and 3D refractive index tomography to obtain time-lapse maps of height, volume, and dry mass in Madin-Darby canine kidney (MDCK) epithelial monolayers undergoing collective motion. This is, to our knowledge, the first systematic use of QPI to quantify epithelial monolayer height, volume, and mass dynamics in situ. From independent measurements of refractive index and height, we determine an average dry mass concentration cd = 0.287 g/ml with 2% variability between cells and over time, demonstrating tight regulation of dry-mass density even during large-amplitude pulsations and density changes. The mean height of the monolayer increases with cell density, while the mean cell volume decreases, revealing contact inhibition of cell size. Pixel- and disc-wise statistics show broad, gamma-like height distributions and strong spatio-temporal height fluctuations that remain substantial at high cell density. Cell-resolved tracking demonstrates that height, area, and volume fluctuate synchronously, with volume changes dominated by area rather than height variations, while dry-mass density remains nearly constant. Dynamic structure-factor analysis reveals subdiffusive dynamics and propagating compression-decompression waves, and a continuum mass-flux analysis shows that the depth-averaged continuity equation fails on cellular scales and is restored only after spatial and temporal coarse-graining. Using simple geometrical models, we show that prismatoid cell shapes with constant true volume can reproduce the observed correlations between height, apical area, and "projected" volume, implying that non-prismatic cell geometry biases 21/2D estimates. Together, these results overturn the assumptions of mass/volume conservation and plug-flow-like monolayer kinematics at cellular scales, and highlight the need to incorporate dry-mass regulation and 3D cell shape into models of epithelial dynamics. SIGNIFICANCE STATEMENTUsing QPI, we provide the first comprehensive and time-resolved characterisation of epithelial monolayer height, volume, and dry mass in situ, yielding quantitative measures that both extend and revise earlier work based on 2D imaging alone. Our measurements challenge two long-standing assumptions in epithelial physics: that cell mass or volume is conserved on the timescales of collective motion, and that monolayers behave as "21/2D" plug-flow sheets with vertical, prism-like cells of equal apical and basal area. These findings necessitate a re-examination of prior experimental interpretations and a reassessment of when existing continuum and cell-based models faithfully describe epithelial monolayer dynamics. They also provide benchmarks for future 3D theories and experiments.

A central problem in soft and biological physics is how molecular-scale activity and remodelling coarse-grain into emergent mechanical laws at larger scales. In growing cell walls (polymeric composite materials that surround 90% of living organisms cells) irreversible deformation is not controlled by elastic stress alone. Instead, growth depends on the interplay between energy storage, dissipation, and the local timing of viscoelastic relaxation. Although dynamic atomic force microscopy (AFM) resolves storage and loss moduli (E', E'') of living walls at nanometre resolution, these observables have remained phenomenological and disconnected from constitutive field variables. Here we introduce a physics-based inversion framework that converts AFM measurements of epidermal cells of living Arabidopsis plants into spatially resolved fields of stiffness k, viscosity , and relaxation time{tau} . By analysing the spatial gradients of E' and E'', we uncover organized mechanical heterogeneities governed by cellular confinement and stress focusing. We demonstrate that the local relaxation time is encoded directly in the coupling between storage and dissipation, yielding the pointwise relation{tau} = (1/{omega}) {partial}E/{partial}E, where{omega} is the indentation frequency. This relation enables model-independent extraction of mechanical timescales and establishes a general route from nanoscale non-equilibrium rheology to continuum descriptions of growth in living and active soft materials. SignificanceHow molecular-scale activity gives rise to tissue-scale form is a central challenge in biological physics. Although growth is fundamentally a non-equilibrium mechanical process, experimental measurements at the nanoscale have not been directly connected to the constitutive parameters that govern morphogenesis. We introduce a framework that converts dynamic atomic force microscopy maps of storage and loss moduli into spatially resolved fields of stiffness, viscosity, and relaxation time in living cell walls. By revealing that mechanical relaxation is encoded in the local coupling between elastic storage and viscous dissipation, our work provides a route from nanoscale rheology to growth-relevant mechanical timing. This establishes a quantitative bridge between molecular remodeling and continuum mechanics, enabling direct experimental constraints on multiscale theories of morphogenesis.

The temporal precision of biochemical oscillators is fundamentally constrained by the energy dissipated to suppress molecular fluctuations, a widely predicted trade-off governing information processing across biology and physics, from molecular motors to kinetic proofreading to computing. Yet, experimental validation in complex biological oscillators remains elusive due to challenges of systematically modulating energy while quantifying stochastic dynamics across large ensembles. Here, we establish a high-throughput droplet-microfluidics platform to reconstitute mitotic oscillations from Xenopus laevis egg extracts within thousands of sub-nanoliter compartments. By precisely tuning ATP across a broad free-energy landscape and developing an analytical framework that decouples intrinsic phase diffusion from quenched period heterogeneity, we uncover a hidden trade-off linking metabolic budget, oscillation speed, and precision. While speed peaks non-monotonically near physiological ATP levels and declines toward both high and low bifurcation limits, precision increases monotonically with energy. These findings provide direct experimental evidence that mitotic timing is actively shaped by energy budgets. Intriguingly, embryonic cell cycles are not optimized for maximum fidelity, but for a metabolic compromise maintaining just enough coherence for synchronous yet rapid divisions, placing the endogenous ATP budget near an energetic optimum balancing speed and accuracy. Our integrated artificial-cell and analytical strategy provides a generalizable framework for mapping thermodynamic limits in non-equilibrium biological dynamics.

Directed cell migration underlies many biological phenomena, from embryonic development to tumor metastasis and organ fibrosis. Most cells typically migrate toward stiffer regions of their extracellular matrix -a behavior known as positive durotaxis. Here we show that culture on rigid plastic reinforces this response, whereas preconditioning in soft 3D physiomimetic environments reprograms migration towards softer environments, a phenomenon known as negative durotaxis. Fetal rat lung fibroblasts preconditioned in 3D physiomimetic hydrogels exhibited negative durotaxis and accumulated near [~]5 kPa, corresponding to the physiological stiffness of the lung. In contrast, genetically identical cells maintained on conventional 2D plastic substrates migrated up stiffness gradients, toward stiffer regions. Although both populations displayed a biphasic force-stiffness relationship, they differed in force magnitude and cytoskeletal organization. Molecular-clutch modeling revealed that durotaxis reversal emerges from two distinct mechanical regimes: a mechanosensitive, high-motor-clutch state that stabilizes adhesions on stiff substrates and drives positive durotaxis, and a low-motor, weak-adhesion state in which clutch slippage on the stiff side causes negative durotaxis. Our results show that durotaxis direction is not an intrinsic cellular property. Rather, it emerges from the interplay between motor activity and adhesion dynamics and can be tuned by culture conditions.

Free-living unicellular organisms known as ciliates rely on fluid flows to perform essential functions. These flows emerge from the coordinated activity of thousands of cilia organized into arrays with highly diverse architectures. Despite the importance of mesoscale cilia organization for flow generation, the relationship between the architecture of the ciliary array and the flow function it performs remains poorly understood. Here, we investigate how the ciliary array in the ciliate Paramecium tetraurelia enables this organism to feed and swim simultaneously. Using expansion microscopy and high-speed imaging, we measure ciliary organization and kinematics, from individual beat dynamics to collective metachronal wave patterns. We find that the cells surface is partitioned into arrays with distinct spatio-temporal patterns that perform specific functions. In addition to the oral apparatus, there are two structurally different domains: a densely ciliated high-frequency beating region located anterior to the oral apparatus and a second domain covering the remainder of the cells surface where cilia are more sparsely distributed and slower-beating. Selective removal of each region results in impaired feeding or swimming, demonstrating the functional specialization of each domain. Together, our findings show that a continuous cilia array can generate flows that perform different functions by locally encoding different ciliary architectures. More broadly, this work highlights spatio-temporal ciliary patterning as a key determinant of array function and provides insight into how organization of ciliary arrays governs swimming and transport in biological systems.

Climbing plants use self-generated oscillatory movements called circumnutations to search their environment for supports to attach to. Yet little is known about what information these movements provide. Here we show that circumnutations enable climbing plants to actively assess the mechanical stability of a newly encountered support and determine whether to initiate twining. Analogous to whisking in mammals, circumnutating shoots generate predictable mechanical loading that probes support resistance. Force measurements of freely circumnutating bean shoots reveal that contact forces follow a characteristic sinusoidal pattern. We develop a minimal physical model of this system, and experimentally informed simulations recover the measured force trajectories. We find that the stem-support interaction is captured by a simple torque balance between external loading and the intrinsic bending moment of the stem, equivalent to a cantilever beam with a rotating load. Analysis of force trajectories, supported by experimentally informed simulations, shows that force amplitude is set by stem stiffness and geometry, whereas the characteristic timescale is governed by the circumnutation rate. Twining occurs only after the stem reaches a critical torque threshold, corresponding to a threshold deformation of the stem that likely serves as the mechanical trigger for twining initiation, reflecting both sufficient support stability and a minimal geometric overshoot required for grasp. Motorized-stage experiments further demonstrate that increasing the effective circumnutation rate accelerates twining initiation to minutes, whereas reducing it can suppress twining despite prolonged contact. Together, these results establish embodied mechanical sensing in plants and show how morphology and self-generated motion enable support selection without centralized control.

Glassy dynamics in active biological cells remain a subject of debate, as cellular activity rarely slows enough for true glassy features to emerge. In this study, we address this paradox of glassy dynamics in epithelial cells by integrating experimental observations with an active vertex model. We demonstrate that while crowding is essential, it is not sufficient for glassy dynamics to emerge. A mechanochemical feedback loop (MCFL), mediated by cell shape changes through the contractile actomyosin network, is required to drive glass transition in dense epithelial tissues, as revealed via a crosstalk between actin-based cell clustering and dynamic heterogeneity in experiments. Incorporating MCFL into the vertex model reveals contrasting results from those previously predicted by theories- we show that the MCFL can counteract cell division-induced fluidisation and enable glassy dynamics to emerge through active cell-to-cell communication. Furthermore, our analysis reveals, for the first time, the existence of novel collective mechanochemical oscillations that arise from the crosstalk of two MCFLs. Together, we demonstrate that an interplay between crowding and active mechanochemical feedback enables the emergence of glass-like traits and collective biochemical oscillations in epithelial tissues with active cell-cell contacts.

Cells sense and respond to the mechanical properties of their environment, yet the minimal physical principles sufficient to reproduce mechanotransduction and durotaxis remain debated. This work introduces FraCeMM, a physics-first mechanochemical simulation framework coupling stochastic ligand-integrin-talin binding to a deformable soft-body cell model on an elastic substrate. Without imposed polarity, directional cues, or migration rules, the model reproduces hallmark mechanobiological behaviors including stiffness-dependent spreading, traction reinforcement, focal adhesion asymmetry, and directed durotaxis. A finite pool of adhesion molecules, mechanically coupled through elastic linkages, drives emergent force asymmetry and polarization via self-consistent feedback between stochastic binding, molecular availability, and substrate stiffness. Despite minimal assumptions and a coarse-grained molecular representation, resulting traction forces, adhesion loads, and migration speeds fall within experimentally reported ranges. These results support the view that local force balance, limited adhesion resources, and mechanically binding are sufficient to generate adaptive mechanosensing and directed migration, establishing a transparent and extensible foundation for computational mechanobiology.

Robust development depends on maintaining correct proportions as overall size varies. What controls and limits this ability to scale remains poorly understood in part due to the complex interplay between mechanical and biochemical factors within developing embryos. Using confinement of dissociated embryonic presomitic mesoderm cells, combined with imaging and chemical perturbations, we identified aggregation as the initial event in de novo anterior-posterior axis patterning. Using a continuum model solely based on cell-cell attraction, we quantitatively map out how the time available for aggregation-driven patterning limits the system size over which scaling can be maintained: Small systems allow for rapid and robust pattern scaling whereas coarsening dynamics substantially de-lay the appearance of a scaled pattern in large systems. Our experiments quantitatively confirm these predicted scaling regimes. Together, our results suggest a developmental time-size tradeoff on the scaling of aggregation-driven patterns.

Receptor-mediated ligand endocytosis is traditionally viewed as a negative feedback mechanism for signal attenuation. Here we show that ligand removal can paradoxically enhance directional information in autonomous cell-cell attraction. Many cell systems migrate toward one another in the absence of externally imposed gradients, implying that secretion, diffusion, and uptake must themselves generate usable directional cues. We develop a surface-resolved theory of a finite-sized detector exposed to a nearby source and derive analytical expressions for the steady-state ligand field. The resulting concentration profiles are governed by a single dimensionless Damkohler number that compares receptor-mediated endocytosis to diffusive ligand transport. Increasing ligand removal lowers extracellular ligand concentrations and reduces absolute concentration differences across the detector surface, but preferentially enhances relative surface anisotropy. Thus, destroying the signal can increase the usable information encoded in relative gradients. Incorporating nonlinear downstream processing reveals a tradeoff between contrast enhancement and signal depletion that yields a well-defined optimal endocytosis rate, in a regime consistent with experimentally measured receptor internalization kinetics. These results recast receptor-mediated endocytosis as an extracellular information-processing mechanism that reshapes self-generated gradients to enhance directional information.

Cells must efficiently locate and engage for tissue formation and immune coordination, yet classical receptor-ligand binding is limited to nanometre distances and is inherently slow [1-3]. Here, we uncover a previously unrecognised physical principle, liquid-like adhesion by phase separation (LAPS). This process creates dynamic wetting layers on cell surfaces [4, 5], functioning as "liquid bridges" that enable robust, long-range cell capture across tens of micrometres. Remarkably, this wetting-mediated attraction remains effective at nanomolar concentrations--conditions where bulk phase separation would not be expected--and facilitates high-fidelity cell sorting through competitive wetting. By integrating aqueous two-phase systems, endogenous proteins (Galectin-3, CCL5), and fluid-particle-dynamics simulations [6], we demonstrate that extracellular liquid-liquid phase separation not only mediates long-range cell capture but also acts as a physical catalyst for contact-dependent signaling. These findings establish extracellular phase separation as a key physical principle complementing molecular recognition in multicellular systems, offering new opportunities for understanding immune response, tissue morphogenesis, and therapeutic strategies targeting the extracellular environment [7, 8].

Cardiac contraction is driven by the collective action of cardiomyocytes, that contain parallel bundles of myofibrils consisting of linear chains of sarcomeres, the basic force-generating units. The dynamics of individual sarcomeres within intact cardiomyocytes remain incompletely understood. While most models assume uniform, synchronized contractions, recent studies hint at unexpected heterogeneity whose origins and significance are not yet clear. By combining the culture of fluorescent sarcomere-reporter hiPSC-derived cardiomyocytes on micropatterned soft gels of different stiffness (5 - 85 kPa) with AI-based tracking of sarcomere motion, we found that increasingly stiff substrates inhibited overall cardiomyocyte contraction, but, surprisingly, did not diminish individual sarcomere dynamics. Instead, sarcomeres competed in a tug-of-war causing increasing heterogeneity, including rapid length oscillations and overextensions (popping). Statistical analysis showed that the heterogeneous dynamics were not caused by static structural differences but were largely stochastic. Stochastic heterogeneity is thus an intrinsic property of cardiac sarcomeres and likely mediates the adaptation of cardiomyocyte contractility to mechanical constraints. A mesoscopic model of coupled sarcomeres shows that these phenomena can be explained by a non-monotonic force-velocity relationship and stochastic fluctuations, where dynamic instability at a critical yielding force creates heterogeneity. Stochastic heterogeneity compensates for structural disorder by randomizing yield events beat-to-beat, preventing damage to specific sarcomeres. Our findings recast cardiac sarcomeres as active, dynamically unstable, and stochastic units engaged in a stochastic tug-of-war, where transient, velocity-dependent forces dominate. We propose that pathological disorder in cardiomyopathy drives a transition from protective stochastic fluctuations to more deterministic, persistently overloaded sarcomeres.

Protein-RNA phase separation gives rise to biomolecular condensates with rich internal organization, yet the molecular rules that connect sequence-encoded interactions and composition to the emergent architecture of these condensates remain poorly defined. Here, using large-scale residue-level coarse-grained simulations, we identify a molecular grammar that governs the formation and stability of multiphase protein-RNA condensates. We show that asymmetries in protein-protein and protein-RNA interactions, together with protein stoichiometry, chain length, and condensate density, collectively determine whether condensates adopt homogeneous, layered, biphasic, or vesicle-like morphologies. Across a broad parameter space, these rules yield hollow multiphase vesicles with dense shells surrounding dilute interiors. Remarkably, vesicular condensates form spontaneously from well-mixed initial conditions, without requiring flux-driven oversaturation or extreme charge imbalance, distinguishing this mechanism from previously proposed routes to condensate hollowing. Our results establish minimal and general design principles for programming internal condensate architecture solely through sequence and composition, and provide a framework for engineering membrane-free vesicles and multilayered condensates with tunable permeability, encapsulation, and responsiveness.

The traditional view of protein self-assembly posits a binary choice between phase separation into fluid condensates and nucleation into crystalline amyloid fibers. However, this framework is incomplete. Experiments show that liquid condensates are non-equilibrium systems that mature into solid-like structures mediated by amphiphilic prion-like domains (PLDs). Being spatially organized yet dynamic, lyotropic phases represent an intermediate regime between these states. Using physics-based de novo protein design (Evo-MD), we identify a vast amphiphilic motif space encoding fluid lyotropic phases (e.g., micelles and bicelles). TEM, CD, and AlphaFold predictions confirm that these motifs also assemble into amyloid-based hydrogels as thermodynamic endpoints. Notably, the molecular grammar of lyotropic motifs overlaps strongly with that of PLDs and LARKS. Thus, while PLDs likely evolved to stabilize condensates through transient interactions near criticality, our results show that these same amphiphilic forces inherently encode lyotropic structuring and subsequent amyloid formation - linking functional condensation with pathological aggregation.

Maintenance of tissue barriers under mechanical stress represents a fundamental biological challenge across organ systems. In the kidney, podocyte cells withstand highly variable hemodynamic forces while preserving a tensioned, nanostructured filtration barrier. Dysregulation of this barrier leads to significant pathology, but the mechanical principles underlying homeostasis of cells against flow of filtrates have not yet been identified. Here, we uncover a counterintuitive mechanical homeostasis mechanism whereby podocyte attachment depends on a dynamic balance between external fluid shear stress and internal cellular contractility. Integrated biomechanical modeling and experiment reveal a previously unrecognized mechanosensing circuit that optimizes integrin distribution at foot process peripheries. Our mathematical framework for cell-matrix adhesion stability reveals, surprisingly, that reducing blood pressure can worsen outcomes when cell contractility is impaired, contrary to clinical belief that lowering blood pressure universally benefits cellular adhesion and kidney function. We validated this principle through mouse models with manipulated blood pressure and myosin inhibition, demonstrating that concurrent reduction of both shear stress and contractility worsens podocyte injury and proteinuria. Super-resolution microscopy confirms our predicted integrin redistribution patterns under these mechanical perturbations. These findings establish a fundamental mechanobiological principle applicable beyond nephrology, and suggest potential treatment pathways targeting non-equilibrium steady states.

Biomolecular condensates govern cellular organization through dynamic, membraneless compartments whose material properties are dictated by intermolecular interactions. While liquid-liquid phase separation enables reversible condensate self-assembly, its dysregulation can trigger the formation of pathological solid-like states, often associated with neurodegenerative disorders. Here, we investigate the molecular mechanisms underlying condensate solidification, focusing on the role of inter-protein {beta}-sheet transitions. Using a minimal protein coarse-grained model, we reveal that the condensates interface acts as a hotspot for inter-protein {beta}-sheet nucleation and growth. Residue- and segment-resolved analyses show that enhanced interfacial mobility, particularly of terminal domains, coupled with locally high protein concentrations, creates optimal conditions for inter-protein {beta}-sheet-sheet formation. Moreover, favourable inter-protein orientational alignment of terminal domains emerges at the interface. We find that asymmetric sequences--e.g. those with defined hydrophobic vs. more hydrophilic regions--further amplify this effect, resulting in local density fluctuations which concentrate aggregation-prone domains at the interface, and collectively promote inter-protein {beta}-sheet transitions. Such amphiphilic interfacial organization is driven by surface-tension minimization, and stabilizes protein structural rearrangements accentuating the spatial bias of inter-protein structural transitions. Altogether, our results demonstrate that general protein polymer-physics models, capturing only essential features such as flexibility and sequence patterning, inherently display condensate solidification at the interface. These findings identify the interface as a central regulator of condensate hardening, linking molecular-scale interactions to mesoscale phase behaviour, and providing mechanistic insight into the spatiotemporal onset of protein dysregulation in membraneless organelles.