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The synthetic pathways of life’s building blocks are envisaged to be through a series of complex prebiotic reactions and processes. However, the strategy to compartmentalize and concentrate biopolymers under prebiotic conditions remains elusive. Liquid-liquid phase separation is a mechanism by which membraneless organelles form inside cells, and has been hypothesized as a potential mechanism for prebiotic compartmentalization. Associative phase separation of oppositely charged species has been shown to partition RNA, but the strongly negative charge exhibited by RNA suggests that RNA-polycation interactions could inhibit RNA folding and its functioning inside the coacervates. Here, we present a prebiotically plausible pathway for non-associative phase separation within an evaporating all-aqueous sessile droplet. We quantitatively investigate the kinetic pathway of phase separation triggered by the non-uniform evaporation rate, together with the Marangoni flow-driven hydrodynamics inside the sessile droplet. With the ability to undergo liquid-liquid phase separation, the drying droplets provide a robust mechanism for formation of prebiotic membraneless compartments, as demonstrated by localization and storage of nucleic acids, in vitro transcription, as well as a three-fold enhancement of ribozyme activity. The compartmentalization mechanism illustrated in this model system is feasible on wet organophilic silica-rich surfaces during early molecular evolution. Prebiotic compartmentalization could prove essential for the evolution of life. Guo et al. show that liquid-liquid separation in an aqueous two-phase system driven by evaporation may already suffice to facilitate chemical processes required for the RNA world hypothesis.

Optical time-stretch imaging enables the continuous capture of non-repetitive events in real time at a line-scan rate of tens of MHz—a distinct advantage for the ultrafast dynamics monitoring and high-throughput screening that are widely needed in biological microscopy. However, its potential is limited by the technical challenge of achieving significant pulse stretching (that is, high temporal dispersion) and low optical loss, which are the critical factors influencing imaging quality, in the visible spectrum demanded in many of these applications. We present a new pulse-stretching technique, termed free-space angular-chirp-enhanced delay (FACED), with three distinguishing features absent in the prevailing dispersive-fiber-based implementations: (1) it generates substantial, reconfigurable temporal dispersion in free space (>1 ns nm −1 ) with low intrinsic loss (<6 dB) at visible wavelengths; (2) its wavelength-invariant pulse-stretching operation introduces a new paradigm in time-stretch imaging, which can now be implemented both with and without spectral encoding; and (3) pulse stretching in FACED inherently provides an ultrafast all-optical laser-beam scanning mechanism at a line-scan rate of tens of MHz. Using FACED, we demonstrate not only ultrafast laser-scanning time-stretch imaging with superior bright-field image quality compared with previous work but also, for the first time, MHz fluorescence and colorized time-stretch microscopy. Our results show that this technique could enable a wider scope of applications in high-speed and high-throughput biological microscopy that were once out of reach. Pulse stretching: stretching achieved at visible wavelengths A new pulse-stretching technique has enabled ultrafast laser-scanning time-stretch imaging to be achieved in the important visible region. Optical time-stretching is used to realize real-time continuous imaging at ultrahigh frame rates, but current technologies based on dispersive fibers are generally restricted to near-infrared wavelengths. Now, a team at the University of Hong Kong led by Kevin Tsia has overcome this limitation by developing a pulse-stretching technique that they dub free-space angular-chirp-enhanced delay. It has the advantages of generating a large dispersion in free space with low loss and of enabling wavelength-invariant stretching. The researchers demonstrated its potential by realizing ultrafast laser-scanning time-stretch imaging with excellent bright-field image quality. They also used it to achieve megahertz fluorescence and color time-stretch microscopy at the optical wavelength of 700 nm.

Overcoming drug resistance is an inevitable challenge to the success of cancer treatment. Recently, in ovarian cancer, a highly chemoresistant tumor, we demonstrated an important role of shear stress in stem-like phenotype and chemoresistance using a three-dimensional microfluidic device, which most closely mimics tumor behavior. Here, we examined a new mechanosensitive microRNA—miR-199a-3p. Unlike most key microRNA biogenesis in static conditions, we found that Dicer, Drosha, and Exportin 5 were not involved in regulating miR-199a-3p under ascitic fluid shear stress (0.02 dynes/cm 2 ). We further showed that hepatocyte growth factor (HGF), but not other ascitic cytokines/growth factors such as epidermal growth factor and tumor necrosis factor α or hypoxia, could transcriptionally downregulate miR-199a-3p through its primary transcript miR-199a-1 and not miR-199a-2. Shear stress in the presence of HGF resulted in a concerted effect via a specific c-Met/PI3K/Akt signaling axis through a positive feedback loop, thereby driving cancer stemness and drug resistance. We also showed that miR-199a-3p expression was inversely correlated with enhanced drug resistance properties in chemoresistant ovarian cancer lines. Patients with low miR-199a-3p expression were more resistant to platinum with a significantly poor prognosis. miR-199a-3p mimic significantly suppressed ovarian tumor metastasis and its co-targeting in combination with cisplatin or paclitaxel further decreased the peritoneal dissemination of ovarian cancer in mice. These findings unravel how biophysical and biochemical cues regulate miR-199a-3p and is important in chemoresistance. miR-199a-3p mimics may serve as a novel targeted therapy for effective chemosensitization.

Periodontal disease is a pervasive and serious health issue, affecting millions globally and leading to severe oral and systemic health complications. This underscores the urgent need to thoroughly understand the complex host-microbe interactions involved. Developing models that allow crosstalk among various bacteria, periodontal component cells, and circulating immune cells is crucial for investigating periodontal disease and discovering new treatments. This study aimed to develop a biomimetic gum tissue model. Within four days, a bio-fabricated tissue with well-established barrier and immune functions was created. In this model, the key periodontal pathogen, Porphyromonas gingivalis, was observed to suppress the recruitment and migration of immune cells and dysregulate CD14 expression in THP-1 cells, leading to significant inflammation and tissue damage. Conversely, the probiotic Akkermansia muciniphila enhanced the host’s defensive immune response, highlighting its potential as a therapeutic agent in periodontal disease.

Organ-specific colonization suggests that specific cell–cell recognition is essential. Yet, very little is known about this particular interaction. Moreover, tumor cell lodgement requires binding under shear stress, but not static, conditions. Here, we successfully isolate the metastatic populations of cancer stem/tumor-initiating cells (M-CSCs). We show that the M-CSCs tether more and roll slower than the non-metastatic (NM)-CSCs, thus resulting in the preferential binding to the peritoneal mesothelium under ascitic fluid shear stress. Mechanistically, this interaction is mediated by P-selectin expressed by the peritoneal mesothelium. Insulin-like growth factor receptor-1 carrying an uncommon non-sulfated sialyl-Lewis x (sLe x ) epitope serves as a distinct P-selectin binding determinant. Several glycosyltransferases, particularly α1,3-fucosyltransferase with rate-limiting activity for sLe x synthesis, are highly expressed in M-CSCs. Tumor xenografts and clinical samples corroborate the relevance of these findings. These data advance our understanding on the molecular regulation of peritoneal metastasis and support the therapeutic potential of targeting the sLe x -P-selectin cascade. Tumor cell in the peritoneum are often exposed to shear forces generated by ascitic flow during metastasis. Here, the authors show that metastatic cancer stem cells tether more and roll slower than the non-metastatic counterparts, and that sialyl-Lewis x -P-selectin axis mediates peritoneal metastasis.

It remains a challenge to produce soft robots that can mimic the responsive adaptability of living organisms. Rather than fabricating soft robots from bulk hydrogels,hydrogels are integrated into the interfacial assembly of aqueous two‐phase systems to generate ultra‐soft and elastic all‐aqueous aquabots that exhibit responsive adaptability, that can shrink on demand and have electrically conductive functions. The adaptive functions of the aquabots provide a new platform to develop minimally invasive surgical devices, targeted drug delivery systems, and flexible electronic sensors and actuators. All‐water‐based aquabots functionalized with responsive hydrogel membranes are ultrasoft and elastic. They can adaptively shrink their size to navigate through much narrower spaces. Also, their electrically conductive membranes enable the fabrication of flexible electronic sensors and actuators.

Engineering heterogeneous hydrogels with distinct phases at various lengths, which resemble biological tissues with high complexity, remains challenging by existing fabricating techniques that require complicated procedures and are often only applicable at bulk scales. Here, inspired by ubiquitous phase separation phenomena in biology, we present a one-step fabrication method based on aqueous phase separation to construct two-aqueous-phase gels that comprise multiple phases with distinct physicochemical properties. The gels fabricated by this approach exhibit enhanced interfacial mechanics compared with their counterparts obtained from conventional layer-by-layer methods. Moreover, two-aqueous-phase gels with programmable structures and tunable physicochemical properties can be conveniently constructed by adjusting the polymer constituents, gelation conditions, and combining different fabrication techniques, such as 3D-printing. The versatility of our approach is demonstrated by mimicking the key features of several biological architectures at different lengths: macroscale muscle-tendon connections; mesoscale cell patterning; microscale molecular compartmentalization. The present work advances the fabrication approach for designing heterogeneous multifunctional materials for various technological and biomedical applications. Preparing heterogeneous hydrogels with distinct phases is desirable for the mimicking of biological tissues, but generally requires complex techniques. Here, the authors report a method that uses phase separation to fabricate two-aqueous phase soft materials with distinct properties at different length scales.

Biomolecular condensates are increasingly recognized for their crucial roles in intracellular organization and the origin of life. Despite their growing importance, efficiently and accurately quantifying condensate volume and concentration remains challenging, hindering the understanding of their properties and functions. Conventional spectroscopy‐based methods for measuring condensate concentration in bulk systems have practical limitations; for example, they require laborious calibration and preparation procedures, large sample volumes, and in vitro analysis. Here, we introduce a microdroplet‐based method that leverages a simple and rapid vortex‐assisted emulsification approach to encapsulate condensates within microdroplets. By determining the microdroplet‐to‐condensate size ratio and partition coefficient in situ, this method enables rapid and calibration‐free quantification of molecular concentrations within condensates. Notably, it reduces processing time by more than tenfold and reduces sample volume and material cost by over two orders of magnitude, while maintaining accuracy comparable to conventional methods. Moreover, this method can precisely quantify subtle variations in condensate volume and concentration under changing environmental conditions, such as salt concentration and stoichiometries. The microdroplet‐based method is anticipated to find broad applicability in fields where precise, efficient, and in situ quantification of condensate volume and concentration is critical, particularly when sample volumes are limited or environmental conditions are dynamic. This work leverages vortex‐generated microdroplets to encapsulate condensates and quantify their volumes and concentrations. Compared to conventional bulk methods, the technique substantially reduces sample volume, cost, and processing time. Its broad utility sheds light on a wide range of applications, particularly those that require high‐throughput and cost‐effective characterization of condensate properties.

Living cells have evolved over billions of years to develop structural and functional complexity with numerous intracellular compartments that are formed due to liquid–liquid phase separation (LLPS). Discovery of the amazing and vital roles of cells in life has sparked tremendous efforts to investigate and replicate the intracellular LLPS. Among them, all‐aqueous emulsions are a minimalistic liquid model that recapitulates the structural and functional features of membraneless organelles and protocells. Here, an emerging all‐aqueous microfluidic technology derived from micrometer‐scaled manipulation of LLPS is presented; the technology enables the state‐of‐art design of advanced biomaterials with exquisite structural proficiency and diversified biological functions. Moreover, a variety of emerging biomedical applications, including encapsulation and delivery of bioactive gradients, fabrication of artificial membraneless organelles, as well as printing and assembly of predesigned cell patterns and living tissues, are inspired by their cellular counterparts. Finally, the challenges and perspectives for further advancing the cell‐inspired all‐aqueous microfluidics toward a more powerful and versatile platform are discussed, particularly regarding new opportunities in multidisciplinary fundamental research and biomedical applications. Inspired by the liquid–liquid phase separation of membraneless organelles, all‐aqueous microfluidics exploit an aqueous two‐phase system to tailor the aqueous structures and shape the formation of materials. This approach is biocompatible for encapsulation, assembly, and patterning of biomolecules and cells in a near‐physiological environment, which enables the state‐of‐art design of advanced biomaterials with exquisite structural proficiency and diversified biological functions.

All-aqueous emulsions exploit spontaneous liquid–liquid separation and due to their water-based nature are particular advantageous for the biocompatible storage and processing of biomacromolecules. However, the ultralow interfacial tensions characteristic of all-aqueous interfaces represent an inherent limitation to the use of thermally adsorbed particles to achieve emulsion stability. Here, we use protein nanofibrils to generate colloidosome-like two-dimensional crosslinked networks of nanostructures templated by all-aqueous emulsions, which we term fibrillosomes. We show that this approach not only allows us to operate below the thermal limit at ultra-low surface tensions but also yields structures that are stable even in the complete absence of an interface. Moreover, we show that the growth and multilayer deposition of fibrils allows us to control the thickness of the capsule shells. These results open up the possibility of stabilizing aqueous two-phase systems using natural proteins, and creating self-standing protein capsules without the requirement for three-phase emulsions or water/oil interfaces. All-aqueous emulsions are useful for delivering and processing biomolecules, but their stability is constrained by low interfacial adsorption energy. Song et al . solve this problem using protein nanofibrils that form a crosslinked network, whose stability is superior to conventional colloidal capsules.