Shape Transformation of Polymer Vesicles.

Life activities, such as respiration, are accomplished through the continuous shape modulation of cells, tissues, and organs. Developing smart materials with shape-morphing capability is a pivotal step toward life-like systems and emerging technologies of wearable electronics, soft robotics, and biomimetic actuators. Drawing inspiration from cells, smart vesicular systems have been assembled to mimic the biological shape modulation. This would enable the understanding of cellular shape adaptation and guide the design of smart materials with shape-morphing capability. Polymer vesicles assembled by amphiphilic molecules are an example of remarkable vesicular systems. The chemical versatility, physical stability, and surface functionality promise their application in nanomedicine, nanoreactor, and biomimetic systems. However, it is difficult to drive polymer vesicles away from equilibrium to induce shape transformation due to the unfavorable energy landscapes caused by the low mobility of polymer chains and low permeability of the vesicular membrane. Extensive studies in the past decades have developed various methods including dialysis, chemical addition, temperature variation, polymerization, gas exchange, etc., to drive shape transformation. Polymer vesicles can now be engineered into a variety of nonspherical shapes. Despite the brilliant progress, most of the current studies regarding the shape transformation of polymer vesicles still lie in the trial-and-error stage. It is a grand challenge to predict and program the shape transformations of polymer vesicles. An in-depth understanding of the deformation pathway of polymer vesicles would facilitate the transition from the trial-and-error stage to the computing stage. In this Account, we introduce recent progress in the shape transformation of polymer vesicles. To provide an insightful analysis, the shape transformation of polymer vesicles is divided into basic and coupled deformation. First, we discuss the basic deformation of polymer vesicles with a focus on two deformation pathways: the oblate pathway and the prolate pathway. Strategies used to trigger different deformation pathways are introduced. Second, we discuss the origin of the selectivity of two deformation pathways and the strategies used to control the selectivity. Third, we discuss the coupled deformation of polymer vesicles with a focus on the switch and coupling of two basic deformation pathways. Last, we analyze the challenges and opportunities in the shape transformation of polymer vesicles. We envision that a systematic understanding of the deformation pathway would push the shape transformation of polymer vesicles from the trial-and-error stage to the computing stage. This would enable the prediction of deformation behaviors of nanoparticles in complex environments, like blood and interstitial tissue, and access to advanced architecture desirable for man-made applications.

Programmable Compartment Networks by Unraveling the Stress-Dependent Deformation of Polymer Vesicles.

Nanocontainers that can sense and respond to environmental stimuli like cells are desirable for next-generation delivery systems. However, it is still a grand challenge for synthetic nanocontainers to mimic or even surpass the shape adaption of cells, which may produce novel compartments for cargo loading. Here, this work reports the engineering of compartment network with a single polymer vesicle by unraveling osmotic stress-dependent deformation. Specifically, by manipulating the way in exerting the stress, sudden increase or gradual increase, polymer vesicles can either undergo deflation into the stomatocyte, a bowl-shaped vesicle enclosing a new compartment, or tubulation into the tubule of varied length. Such stress-dependent deformation inspired us to program the shape transformation of polymer vesicles, including tubulation, deflation, or first tubulation and then deflation. The coupled deformation successfully transforms the polymer vesicle into the stomatocyte with tubular arms and a network of two or three small stomatocytes connected by tubules. To the author's knowledge, these morphologies are still not accessed by synthetic nanocontainers. This work envisions that the network of stomatocytes may enable the loading of different catalysts to construct novel motile systems, and the well-defined morphology of vesicles helps to define the effect of morphology on cellar uptake.

The average magnetic anisotropy of polystyrene in polymersomes self-assembled from poly(ethylene glycol)-b-polystyrene.

Using the diamagnetic anisotropy of polymers for the characterization of polymers and polymer aggregates is a relatively new approach in the field of soft-matter and polymer research. So far, a good and thorough quantitative description of these diamagnetic properties has been lacking. Using a simple equation that links the magnetic properties of an average polymer repeating unit to those of the polymer vesicle of any shape, we measured, using magnetic birefringence, the average diamagnetic anisotropy of a polystyrene (PS) repeating unit, ΔχPS, inside a poly(ethylene glycol)-polystyrene (PEG-PS) polymersome membrane as a function of the PS-length and as a function of the preparation method. All obtained values of ΔχPS have a negative sign which results in polymers tending to align perpendicular to an applied magnetic field. Combined, the same order of magnitude of ΔχPS (10-12 m3 mol-1) for all polymersome shapes proves that the individual polymers are organized similarly regardless of the PS length and polymersome shape. Furthermore, the value found is only a fraction (∼1%) of what it can maximally be due to the random coiling of the polymers. We, therefore, predict that further ordering of the polymers within the membrane could lead to similar responses at much lower magnetic fields, possibly obtainable with permanent magnets, which would be highly advantageous for practical applications.

Unveiling the Antifouling Potential of Stabilized Poly(phosphorus ylides).

Zwitterionic polymers have emerged as highly attractive building blocks for antifouling coatings in biomedical applications. Notably, these polymers offer effective alternatives to the widely used poly(ethylene glycol) (PEG), which has raised concerns regarding its immunotoxicity and the development of PEG-specific antibodies. Polymeric ylides, a largely overlooked class of zwitterionic polymers, have been reported as effective antifouling scaffolds. However, the reported subclasses, poly(sulfur ylides) and N-oxides, lack structural diversity and chemical variability. In this study, we present the synthesis and characterization of polymeric phosphorus ylides as an unexplored class of poly(ylides) with significantly increased structural diversity, which is of high value when designing future ylide-based antifouling materials. Our findings demonstrate that, owing to their low dipole moments and hydration layers, these polymeric phosphorus ylides significantly reduce bacterial attachment. Furthermore, we observe selective toxicity toward bacteria rather than mammalian cells. The bactericidal nature of poly(phosphorus ylides), coupled with their expanded chemical space, provides a distinct advantage over existing materials, including zwitterionic polymers from betaine scaffolds. We anticipate that these unexplored structures will broaden the scope of antifouling applications for poly(ylides).

Porous Polymersomes as Carriers for Silver Nanoparticles and Nanoclusters: Advantages of Compartmentalization for Antimicrobial Usage.

The global threat to public health posed by antibiotic-resistant bacterial infections requires the exploration of innovative approaches. Nanomaterials, particularly silver nanoparticles (AgNPs) and nanoclusters (AgNCs), have emerged as potential solutions to address the pressing issue of a bacterial healthcare crisis. However, the high cytotoxicity levels and low stability associated with AgNPs and AgNCs limit their applicability. To overcome these challenges, AgNCs and AgNPs were synthesized in the presence of porous polymersomes, resulting in a compartmentalized system that enhances stability, reduces cytotoxicity, and maintains high antimicrobial activity. The encapsulated particles exhibit a distribution of silver components on both the surface and the core, which is confirmed through the analysis of surface charge and center of mass. Moreover, our investigation demonstrates improved stability of the nanoparticles and nanoclusters upon entrapment in the porous system, as evidenced by the ion release assay. The antimicrobial effectiveness of porous polymersomes containing AgNPs and AgNCs was demonstrated by visualizing the biofilms and quantifying the penetration depth. Furthermore, cytotoxicity studies showed that compartmentalization increases cell compatibility for AgNC-based systems, showcasing the many advantages this system holds.

Microfluidic Design of Streamlined Alginate Hydrogel Micromotors with Run and Tumble Motion Patterns.

Autonomous micromotors demonstrate remarkable advancements in biomedical applications. A noteworthy example is streamlined motors, which display enhanced movement efficiency with low fluid-resistance. However, existing streamlined motors, primarily constructed from inorganic materials, present challenges due to their complex fabrication procedures and lack of a soft interface for interaction with biological systems. Herein, a novel design of biodegradable streamlined alginate hydrogel micromotors with a teardrop shape by microfluidics is introduced. The platform enables the high-throughput fabrication of monodisperse micromotors with varied dimensions. By incorporating Pt-coated Fe3 O4 nanoparticles, micromotors are equipped with dual capabilities of catalytic propulsion and accurate magnetic guidance. Through precisely tuning the localization regions of catalysts within the micromotors, the streamlined hydrogel micromotors not only exhibit enhanced propelling efficiency, but also accomplish distinct motion patterns of run and tumble. The design provides insights for developing advanced micromotors capable of executing intricate tasks across diverse application scenarios.

Zwitterionic Polymeric Sulfur Ylides with Minimal Charge Separation Open a New Generation of Antifouling and Bactericidal Materials.

Zwitterionic polymers are widely employed hydrophilic building blocks for antifouling coatings with numerous applications across a wide range of fields, including but not limited to biomedical science, drug delivery and nanotechnology. Zwitterionic polymers are considered as an attractive alternative to polyethylene glycol because of their biocompatibility and effectiveness to prevent formation of biofilms. To this end, zwitterionic polymers are classified in two categories, namely polybetaines and polyampholytes. Yet, despite a fundamental interest to drive the development of new antifouling materials, the chemical composition of zwitterionic polymer remains severely limited. Here, we show that poly(sulfur ylides) that belong to the largely overlooked class of poly(ylides), effectively prevent the formation of biofilms from pathogenic bacteria. While surface energy analysis reveals strong hydrogen-bond acceptor capabilities of poly(sulfur ylide), membrane damage of pathogenic bacteria induced by poly(sulfur ylides) indicates toxicity towards bacteria while not affecting eucaryotic cells. Such synergistic effect of poly(sulfur ylides) offers distinct advantages over polyethylene glycol when designing new antifouling materials. We expect that our findings will pave the way for the development of a range of ylide-based materials with antifouling properties that have yet to be explored, opening up new directions at the interface of chemistry, biology, and material science.

Directed Neural Stem Cells Differentiation via Signal Communication with Ni-Zn Micromotors.

Neural stem cells (NSCs), with the capability of self-renewal, differentiation, and environment modulation, are considered promising for stroke, brain injury therapy, and neuron regeneration. Activation of endogenous NSCs, is attracting increasing research enthusiasm, which avoids immune rejection and ethical issues of exogenous cell transplantation. Yet, how to induce directed growth and differentiation in situ remain a major challenge. In this study, a pure water-driven Ni-Zn micromotor via a self-established electric-chemical field is proposed. The micromotors can be magnetically guided and precisely approach target NSCs. Through the electric-chemical field, bioelectrical signal exchange and communication with endogenous NSCs are allowed, thus allowing for regulated proliferation and directed neuron differentiation in vivo. Therefore, the Ni-Zn micromotor provides a platform for controlling cell fate via a self-established electrochemical field and targeted activation of endogenous NSCs.

Nanorobot-Mediated Synchronized Neuron Activation.

Interactions between active materials lead to collective behavior and even intelligence beyond the capability of individuals. Such behaviors are prevalent in nature and can be observed in animal colonies, providing these species with diverse capacities for communication and cooperation. In artificial systems, however, collective intelligence systems interacting with biological entities remains unexplored. Herein, we describe black (B)-TiO2@N/Au nanorobots interacting through photocatalytic pure water splitting-induced electrophoresis that exhibit periodic swarming oscillations under programmed near-infrared light. The periodic chemical-electric field generated by the oscillating B-TiO2@N/Au nanorobot swarm leads to local neuron activation in vitro. The field oscillations and neurotransmission from synchronized neurons further trigger the resonance oscillation of neuron populations without synaptic contact (about 2 mm spacing), in different ways from normal neuron oscillation requiring direct contact. We envision that the oscillating nanorobot swarm platforms will shed light on contactless communication of neurons and offer tools to explore interactions between neurons.

Complex Energy Landscapes of Self-Assembled Vesicles.

The field of supramolecular chemistry has witnessed tremendous progress in bringing the system away from equilibrium for traditionally inaccessible structures and functions. Vesicular assemblies with complex energy landscapes and pathways, which are reminiscent of diverse cellular vesicles like exosomes, remain exceedingly rare. Here, relying on the activation of oligo(ethylene glycol) (OEG) interdigitation and the encoded conformational freedom in monodisperse Janus dendrimers, we reveal a rich landscape and a pathway selection of distinct vesicles. The interdigitation can be selectively switched on and off using temperature ramps, and the critical temperatures can be further determined by molecular design. Our findings suggest that synthetic vesicles, with different energy states and unexpected transition pathways, emulate dynamic cellular vesicles in nature. We anticipate that vesicles with an activated OEG corona conformation will open new routes for nanomedicine and advanced materials.

Morphogenesis of starfish polymersomes.

The enhanced membrane stability and chemical versatility of polymeric vesicles have made them promising tools in micro/nanoreactors, drug delivery, cell mimicking, etc. However, shape control over polymersomes remains a challenge and has restricted their full potential. Here we show that local curvature formation on the polymeric membrane can be controlled by applying poly(N-isopropylacrylamide) as a responsive hydrophobic unit, while adding salt ions to modulate the properties of poly(N-isopropylacrylamide) and its interaction with the polymeric membrane. Polymersomes with multiple arms are fabricated, and the number of arms could be tuned by salt concentration. Furthermore, the salt ions are shown to have a thermodynamic effect on the insertion of poly(N-isopropylacrylamide) into the polymeric membrane. This controlled shape transformation can provide evidence for studying the role of salt ions in curvature formation on polymeric membranes and biomembranes. Moreover, potential stimuli-responsive non-spherical polymersomes can be good candidates for various applications, especially in nanomedicine.

Anisotropic, Hydrogel Microparticles as pH-Responsive Drug Carriers for Oral Administration of 5-FU.

In the last 20 years, the development of stimuli-responsive drug delivery systems (DDS) has received great attention. Hydrogel microparticles represent one of the candidates with the most potential. However, if the role of the cross-linking method, polymer composition, and concentration on their performance as DDS has been well-studied, still, a lot needs to be explained regarding the effect caused by the morphology. To investigate this, herein, we report the fabrication of PEGDA-ALMA-based microgels with spherical and asymmetric shapes for 5-fluorouracil (5-FU) on-demand loading and in vitro pH-triggered release. Due to anisotropic properties, the asymmetric particles showed an increased drug adsorption and higher pH responsiveness, which in turn led to a higher desorption efficacy at the target pH environment, making them an ideal candidate for oral administration of 5-FU in colorectal cancer. The cytotoxicity of empty spherical microgels was higher than the cytotoxicity of empty asymmetric microgels, suggesting that the gel network's mechanical proprieties of anisotropic particles were a better three-dimensional environment for the vital functions of cells. Upon treatment with drug-loaded microgels, the HeLa cells' viability was lower after incubation with asymmetric particles, confirming a minor release of 5-FU from spherical particles.

Surface-Area Determination of Anisotropic Polymersomes by Amphiphilic Molecular Probe Loading.

The surface area of anisotropic polymeric assemblies is a critical parameter concerning their properties. However, it is still a grand challenge for traditional techniques to determine the surface area. Here, a molecular probe loading (MPL) method is developed to measure the surface area of anisotropic polymersomes in the shape of tube, disc, and stomatocyte. This method uses an amphiphilic molecular probe, comprising hydrophobic pyrene as the anchor and hydrophilic tetraethylene glycol (EG4 ) as the float. The surface area of spherical polymersomes determined by dynamic light scattering is quantitatively correlated with the loading amount of probes, allowing the calculation of the average separation distance between the loaded probes. With the separation distance, we successfully determine the surface area of anisotropic polymersomes by measuring the loading amount. We envision that the MPL method will assist in the real-time surface area characterization, enabling the customization of functions.

Molecular Engineering of pH-Responsive Anchoring Systems onto Poly(ethylene glycol) Corona.

An adaptive surface that can sense and respond to environmental stimuli is integral to smart functional materials. Here, we report pH-responsive anchoring systems onto the poly(ethylene glycol) (PEG) corona of polymer vesicles. The hydrophobic anchor, pyrene, is reversibly inserted into the PEG corona through the reversible protonation of its covalently linked pH-sensing group. Depending on the pKa of the sensor, the pH-responsive region is engineered from acidic to neutral and basic conditions. The switchable electrostatic repulsion between the sensors contributes to the responsive anchoring behavior. Our findings provide a new responsive binding chemistry for the creation of smart nanomedicine and a nanoreactor.

Medical micro- and nanomotors in the body.

Attributed to the miniaturized body size and active mobility, micro- and nanomotors (MNMs) have demonstrated tremendous potential for medical applications. However, from bench to bedside, massive efforts are needed to address critical issues, such as cost-effective fabrication, on-demand integration of multiple functions, biocompatibility, biodegradability, controlled propulsion and in vivo navigation. Herein, we summarize the advances of biomedical MNMs reported in the past two decades, with particular emphasis on the design, fabrication, propulsion, navigation, and the abilities of biological barriers penetration, biosensing, diagnosis, minimally invasive surgery and targeted cargo delivery. Future perspectives and challenges are discussed as well. This review can lay the foundation for the future direction of medical MNMs, pushing one step forward on the road to achieving practical theranostics using MNMs.

Selective photodimerization of acenaphthylene in polymersome nanoreactors.

PEG-b-PLA polymersomes are used as nanoreactors for the photodimerization of acenaphthylene (ACE), increasing reaction rate significantly. The reaction steered towards almost exclusive formation of anti product (94 : 6). This selectivity is remarkable, as other known systems commonly mediate formation of the syn product.

Adaptive particle patterning in the presence of active synthetic nanomotors.

For the maintenance of a biological system, spatial organization of material condensates within the cell through the dissipation of energy is crucial. Besides directed transport via microtubules, material arrangement can be achieved via motor protein facilitated adaptive active diffusiophoresis. For example, the distribution of membrane proteins during the cell division of Escherichia coli is affected by the MinD system. Synthetic active motors exhibit the ability to simulate natural motors. Here we propose an active Au-Zn nanomotor driven by water and discovered an interesting adaptive interaction mode of the diffusiophoretic Au-Zn nanomotors with passive condensate particles in different environments. It is found that the attraction/repulsion between the nanomotor and passive particles is adaptive, while an interesting hollow pattern is formed with a negatively charged substrate and a cluster pattern is favored with a positively charged substrate.

Spatial Control over Catalyst Positioning for Increased Micromotor Efficiency.

Motion is influenced by many different aspects of a micromotor's design, such as shape, roughness and the type of materials used. When designing a motor, asymmetry is the main requirement to take into account, either in shape or in catalyst distribution. It influences both speed and directionality since it dictates the location of propulsion force. Here, we combine asymmetry in shape and asymmetry in catalyst distribution to study the motion of soft micromotors. A microfluidic method is utilized to generate aqueous double emulsions, which upon UV-exposure form asymmetric microgels. Taking advantage of the flexibility of this method, we fabricated micromotors with homogeneous catalyst distribution throughout the microbead and micromotors with different degrees of catalyst localization within the active site. Spatial control over catalyst positioning is advantageous since less enzyme is needed for the same propulsion speed as the homogeneous system and it provides further confinement and compartmentalization of the catalyst. This proof-of-concept of our new design will make the use of enzymes as driving forces for motors more accessible, as well as providing a new route for compartmentalizing enzymes at interfaces without the need for catalyst-specific functionalization.

Adaptive insertion of a hydrophobic anchor into a poly(ethylene glycol) host for programmable surface functionalization.

Covalent and non-covalent molecular binding are two strategies to tailor surface properties and functions. However, the lack of responsiveness and requirement for specific binding groups makes spatiotemporal control challenging. Here, we report the adaptive insertion of a hydrophobic anchor into a poly(ethylene glycol) (PEG) host as a non-covalent binding strategy for surface functionalization. By using polycyclic aromatic hydrocarbons as the hydrophobic anchor, hydrophilic charged and non-charged functional modules were spontaneously loaded onto PEG corona in 2 min without the assistance of any catalysts and binding groups. The thermodynamically favourable insertion of the hydrophobic anchor can be reversed by pulling the functional module, enabling programmable surface functionalization. We anticipate that the adaptive molecular recognition between the hydrophobic anchor and the PEG host will challenge the hydrophilic understanding of PEG and enhance the progress in nanomedicine, advanced materials and nanotechnology.

Reversible speed control of one-stimulus-double-response, temperature-sensitive asymmetric hydrogel micromotors.

Soft, one-stimulus-double-response, thermo-sensitive, PNIPAm-based microgels are designed for controlled autonomous motion under stimuli. At higher temperature, the motors with physically encapsulated catalase move faster, while motors in which catalase is chemically linked to PNIPAm ceased moving. The phenomenon is reversible over multiple cycles of temperature.