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.

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.

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.

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.

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.

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.

Micro-Nano Motors with Taxis Behavior: Principles, Designs, and Biomedical Applications.

As a novel mobile nanodevice, micro-nano motors (MNMs) can convert the energy of the surrounding environment into mechanical motion. With this unique ability, they promise revolutionary potential in bio-applications including precise drug delivery, bio-sensing, and noninvasive surgery. Yet for practically reaching the target and fulfilling these tasks in dynamically changing bio-environment, environment adaptivity beyond propulsion is important yet challenging. MNMs with taxis behavior/autonomous target-seeking ability offer a desirable solution. These motors can adaptively move to the target location and complete the task. Thanks to the persistent efforts of researchers, tactic MNMs have shown automatic navigation to target under various energy fields, not only in static environments, but also in shear rheological conditions that simulate blood flow. Therefore, tactic motors with self-targeting capability lay a concrete foundation for targeted drug delivery, cell transplantation, and thrombus ablation. This review systematically presents the moving principle, design, and biological applications of tactic MNMs under different energy fields. Through in-depth analysis of state-of-art progress, the obstacles of the field and possible solutions are discussed. With the continuous innovation and breakthroughs of multi-disciplinary researchers, MNMs with taxis behavior are expected to provide a revolutionary solution for cancer and other major diseases in the biomedical field.

Control the Neural Stem Cell Fate with Biohybrid Piezoelectrical Magnetite Micromotors.

Inducing neural stem cells to differentiate and replace degenerated functional neurons represents the most promising approach for neural degenerative diseases including Parkinson's disease, Alzheimer's disease, etc. While diverse strategies have been proposed in recent years, most of these are hindered due to uncontrollable cell fate and device invasiveness. Here, we report a minimally invasive micromotor platform with biodegradable helical Spirulina plantensis (S. platensis) as the framework and superparamagnetic Fe3O4 nanoparticles/piezoelectric BaTiO3 nanoparticles as the built-in function units. With a low-strength rotational magnetic field, this integrated micromotor system can perform precise navigation in biofluid and achieve single-neural stem cell targeting. Remarkably, by tuning ultrasound intensity, thus the local electrical output by the motor, directed differentiation of the neural stem cell into astrocytes, functional neurons (dopamine neurons, cholinergic neurons), and oligodendrocytes, can be achieved. This micromotor platform can serve as a highly controllable wireless tool for bioelectronics and neuronal regenerative therapy.

Apoptotic Tumor DNA Activated Nanomotor Chemotaxis.

Inspired by the tactic organisms in Nature that can self-direct their movement following environmental stimulus gradient, we proposed a DNase functionalized Janus nanoparticle (JNP) nanomotor system for the first time, which can be powered by ultralow nM to µM levels of DNA. The system exhibited interesting chemotactic behavior toward a DNA richer area, which is physiologically related with many diseases including tumors. In the presence of the subtle DNA gradient generated by apoptotic tumor cells, the cargo loaded nanomotors were able to sense the DNA signal released by the cells and demonstrate directional motion toward tumor cells. For our system, the subtle DNA gradient by a small amount (10 µL) of tumor cells is sufficient to induce the chemotaxis behavior of self-navigating and self-targeting ability of our nanomotor system, which promises to shed new light for tumor diagnosis and therapy.

Exploring New Horizons in Liquid Compartmentalization via Microfluidics.

Spatial organization of cellular processes is crucial to efficiently regulate life's essential reactions. Nature does this by compartmentalization, either using membranes, such as the cell and nuclear membrane, or by liquid-like droplets formed by aqueous liquid-liquid phase separation. Aqueous liquid-liquid phase separation can be divided in two different phenomena, associative and segregative phase separation, of which both are studied for their membraneless compartmentalization abilities. For centuries, segregative phase separation has been used for the extraction and purification of biomolecules. With the emergence of microfluidic techniques, further exciting possibilities were explored because of their ability to fine-tune phase separation within emulsions of various compositions and morphologies and achieve one of the simplest forms of compartmentalization. Lately, interest in aqueous liquid-liquid phase separation has been revived due to the discovery of membraneless phases within the cell. In this Perspective we focus on segregative aqueous phase separation, discuss the theory of this interesting phenomenon, and give an overview of the evolution of aqueous phase separation in microfluidics.

Membrane folding and shape transformation in biomimetic vesicles.

Polymeric self-assembled structures have been a topic of interest in the last few decades, specifically for the use of biomedical applications, such as drug delivery. It is exciting to investigate the formation of various shapes and sizes of such structures, as the morphology is crucial for their function. In this manuscript the important factors to control the morphology during self-assembly and subsequent shape transformation processes are discussed. We describe the main parameters to control and show the practical application of these parameters on biodegradable amphiphilic PEG-PDLLA block-copolymers. Thereby a variety of different morphologies, including micelles, worms, LCVs, discs, rods, stomatocytes, nested vesicles, and spherical vesicles of various sizes are created using only four diblock-copolymers and with careful tuning of two organic solvents. Further advances will lead to formation of more complex structures.

Micro-/Nanomotors toward Biomedical Applications: The Recent Progress in Biocompatibility.

Inspired by the highly versatile natural motors, artificial micro-/nanomotors that can convert surrounding energies into mechanical motion and accomplish multiple tasks are devised. In the past few years, micro-/nanomotors have demonstrated significant potential in biomedicine. However, the practical biomedical applications of these small-scale devices are still at an infant stage. For successful bench-to-bed translation, biocompatibility of micro-/nanomotor systems is the central issue to be considered. Herein, the recent progress in micro-/nanomotors in biocompatibility is reviewed, with a special focus on their biomedical applications. Through close collaboration between researches in the nanoengineering, material chemistry, and biomedical fields, it is expected that a promising real-world application platform based on micro-/nanomotors will emerge in the near future.

Tailoring Polymersome Shape Using the Hofmeister Effect.

Reshaping polymersomes remains a challenge for both size and shape control, methodology development, and mechanism understanding, which hindered their application in nanomedicine and nanomachine. Unlike liposome, polymersomes are capable of maintaining their shape due to their rigid and glassy membrane. Here we use the Hofmeister effect to guide the shape control of polymersome by tuning the ion type and concentration. Multiple morphologies such as ellipsoid, tube, disc, stomatocytes, and large compound vesicles are found. These results give evidence of demonstrating that the shape changes are not only induced by osmotic pressure, but also by the interaction with the polymersome membranes. Additionally, this methodology provides a general tool to tailor the shape of polymersome into various morphologies.

Modular Approach to the Functionalization of Polymersomes.

Functionalizing polymersomes remains a challenge due to the limitation in reaction conditions applicable to the chemistry on the surface, hindering their application for selective targeting. In order to overcome this limitation, functionalization can be introduced right before the self-assembly. Here, we have synthesized a library (32 examples) of PEG-b-PS and PEG-b-PDLLA with various functional groups derived from the amine-functionalized polymers, leading to functionally active polymersomes. We show that polymersome formation is possible via the general method with all functionalized groups and that these handles are present on the surface and are able to undergo reactions. Additionally, this methodology provides a general synthetic tool to tailor the functional group of the polymersome right before self-assembly, without limitation on the reaction conditions.

Supramolecular Spheres Self-Assembled from Conical Dendrons Are Chiral.

Frank-Kasper phases and liquid quasicrystals self-organize from supramolecular spheres of dendrimers, block copolymers, surfactants and other self-assembling molecules. These spheres are expected to be achiral due to their isotropic shape. Nevertheless, supramolecular spheres from short helical stacks of crown-like dendrimers self-organize a Pm3̅ n cubic (Frank-Kasper A15) phase which exhibits chirality on the macroscopic scale. However, the chirality of classic isotropic supramolecular micellar-like spheres, generated from conical dendrons, is unknown. Here we report a library of second and third generation biphenylpropyl dendrons with chiral groups at their apex that produces single-handed chiral supramolecular spheres. Up to 480 conical dendrons self-assemble to form micellar-like spheres, with a molar mass of up to 1.1 × 106 g/mol, that self-organize into a Pm3̅ n phase with chirality detectable on the macroscopic scale. This demonstration of chirality in micellar-like spheres of a Frank-Kasper phase raises the fundamental question whether micellar-like spheres forming 3D phases generated from other soft matter such as block copolymers, surfactants, and other molecules are chiral.

A Supramolecular Approach to Nanoscale Motion: Polymersome-Based Self-Propelled Nanomotors.

Autonomous micro- and nanoscale systems have revolutionized the way scientists look into the future, opening up new frontiers to approach and solve problems via a more bioinspired route. However, to achieve systems with higher complexity, superior output control, and multifunctionality, an in-depth study of the different factors that affect micro- and nanomotor behavior is crucial. From a fundamental perspective, the mechanical response of micro- and nanomotors still requires further study in order to have a better understanding of how exactly these systems operate and the different mechanisms of motion that can be combined into one system to achieve an optimal response. From a design engineering point of view, compatibility, degradability, specificity, sensitivity, responsiveness, and efficiency of the active systems fabricated to this point have to be addressed, with respect to the potential of these devices for biomedical applications. Nonetheless, optimizing the system with regards to all these areas is a challenging task with the micro- and nanomotors studied to date, as most of them consist of materials or designs that are unfavorable for further chemical or physical manipulation. As this new field of self-powered systems moves forward, the need for motor prototypes with different sizes, shapes, chemical functionalities, and architectures becomes increasingly important and will define not only the way active systems are powered, but also the methods for motor fabrication. Bottom-up supramolecular approaches have recently emerged as great candidates for the development of active structures that allow for chemical or physical functionalization, shape transformation, and compartmentalization, in a structure that provides a soft interface to improve molecular recognition and cell uptake. Our group pioneers the use of supramolecular structures as catalytically propelled systems via the fabrication of stomatocyte or tubular-shaped motors capable of displaying active motion in a substrate concentration-dependent fashion. This behavior demonstrates the potential of bottom-up assemblies for powering motion at the micro- or nanoscale, with a system that can be readily tuned and controlled at the molecular level. In this Account, we highlight the steps we have taken in order to understand and optimize the design of catalytically powered polymersome-based motors. Our research has been focused on addressing the importance of motor architecture, motion activation, direction control, and biological integration. While our work supports the feasibility of supramolecular structures for the design of active systems, we strongly believe that we are still in the initial stages of unveiling the full potential of supramolecular chemistry in the micro- and nanomotor field. We look forward to using this approach for the development of multifunctional and stimuli-responsive systems in the near future.

Fabrication of Self-Propelled Micro- and Nanomotors Based on Janus Structures.

Delicate molecular and biological motors are tiny machines capable of achieving numerous vital tasks in biological processes. To gain a deeper understanding of their mechanism of motion, researchers from multiple backgrounds have designed and fabricated artificial micro- and nanomotors. These nano-/microscale motors can self-propel in solution by exploiting different sources of energy; thus showing tremendous potential in widespread applications. As one of the most common motor systems, Janus motors possess unique asymmetric structures and integrate different functional materials onto two sides. This review mainly focuses on the fabrication of different types of micro- and nanomotors based on Janus structures. Furthermore, some challenges still exist in the implementation of Janus motors in the biomedical field. With such common goals in mind, it is expected that the elaborate and multifunctional design of Janus motors will overcome their challenges in the near future.

Active, Autonomous, and Adaptive Polymeric Particles for Biomedical Applications.

Nature's motors are complex and efficient systems, which are able to respond to many different stimuli present in the cell. Nanomotors for biomedical applications are designed to mimic nature's complexity; however, they usually lack biocompatibility and the ability to adapt to their environment. Polymeric vesicles can overcome these problems due to the soft and flexible nature of polymers. Herein we will highlight the recent progress and the crucial steps needed to fabricate active and adaptive motor systems for their use in biomedical applications and our approach to reach this goal. This includes the formation of active, asymmetric vesicles and the incorporation of a catalyst, together with their potential in biological applications and the challenges still to overcome.

Screening Libraries of Amphiphilic Janus Dendrimers Based on Natural Phenolic Acids to Discover Monodisperse Unilamellar Dendrimersomes.

Natural, including plant, and synthetic phenolic acids are employed as building blocks for the synthesis of constitutional isomeric libraries of self-assembling dendrons and dendrimers that are the simplest examples of programmed synthetic macromolecules. Amphiphilic Janus dendrimers are synthesized from a diversity of building blocks including natural phenolic acids. They self-assemble in water or buffer into vesicular dendrimersomes employed as biological membrane mimics, hybrid and synthetic cells. These dendrimersomes are predominantly uni- or multilamellar vesicles with size and polydispersity that is predicted by their primary structure. However, in numerous cases, unilamellar dendrimersomes completely free of multilamellar assemblies are desirable. Here, we report the synthesis and structural analysis of a library containing 13 amphiphilic Janus dendrimers containing linear and branched alkyl chains on their hydrophobic part. They were prepared by an optimized iterative modular synthesis starting from natural phenolic acids. Monodisperse dendrimersomes were prepared by injection and giant polydisperse by hydration. Both were structurally characterized to select the molecular design principles that provide unilamellar dendrimersomes in higher yields and shorter reaction times than under previously used reaction conditions. These dendrimersomes are expected to provide important tools for synthetic cell biology, encapsulation, and delivery.