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.

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.

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.

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.

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.

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.

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.

Supramolecular nanomotors with "pH taxis" for active drug delivery in the tumor microenvironment.

Self-propelled nanomotors demonstrating autonomous motion in biologically relevant fuel are currently being studied to overcome the use of external physical or chemical stimuli as precise delivery agents. In this context, the tumor microenvironment (TME) with slightly acidic pH is used for developing cargo-releasing artificial systems triggered by such conditions. However, there is still a need for fabrication of smart nanomotors that can sense the acidic pH prevalent in the TME rather than using an external fuel source for selective activation and thereafter migrating towards tumors for active drug delivery. Herein, supramolecular assembly-based nanomotors are fabricated by in-situ grown CaCO3 nanoparticles and studied for their motility behaviour in endogenously generated acidic pH by HeLa cells and further exploited as an active delivery vehicle for DOX molecules to the cells for their anticancer efficacy. The nanomotors are activated in slightly acidic pH showcasing "pH taxis" towards tumor cells without the need for any sophisticated/complicated technologies or an external fuel source for active and targeted delivery of drugs.

Stimulus-responsive nanomotors based on gated enzyme-powered Janus Au-mesoporous silica nanoparticles for enhanced cargo delivery.

Here we report functional stimulus-responsive nanomotors based on Janus Au-mesoporous silica nanoparticles capable of self-propelling via the biocatalytic conversion of chemical fuel, that read information from the environment (the presence of glutathione) and accordingly deliver a cargo.

Micro/nanomotors towards in vivo application: cell, tissue and biofluid.

Inspired by highly efficient natural motors, synthetic micro/nanomotors are self-propelled machines capable of converting the supplied fuel into mechanical motion. A significant advance has been made in the construction of diverse motors over the last decade. These synthetic motor systems, with rapid transporting and efficient cargo towing abilities, are expected to open up new horizons for various applications. Utilizing emergent motor platforms for in vivo applications is one important aspect receiving growing interest as conventional therapeutic methodology still remains limited for cancer, heart, or vasculature diseases. In this review we will highlight the recent efforts towards realistic in vivo application of various motor systems. With ever booming research enthusiasm in this field and increasing multidisciplinary cooperation, micro/nanomotors with integrated multifunctionality and selectivity are on their way to revolutionize clinical practice.

Redox-Sensitive Stomatocyte Nanomotors: Destruction and Drug Release in the Presence of Glutathione.

The development of artificial nanomotor systems that are stimuli-responsive is still posing many challenges. Herein, we demonstrate the self-assembly of a redox-responsive stomatocyte nanomotor system, which can be used for triggered drug release under biological reducing conditions. The redox sensitivity was introduced by incorporating a disulfide bridge between the hydrophilic poly(ethylene glycol) block and the hydrophobic polystyrene block. When incubated with the endogenous reducing agent glutathione at a concentration comparable to that within cells, the external PEG shells of these stimuli-responsive nanomotors are cleaved. The specific bowl-shaped stomatocytes aggregate after the treatment with glutathione, leading to the loss of motion and triggered drug release. These novel redox-responsive nanomotors can not only be used for remote transport but also for drug delivery, which is promising for future biomedical applications.

Biodegradable Hybrid Stomatocyte Nanomotors for Drug Delivery.

We report the self-assembly of a biodegradable platinum nanoparticle-loaded stomatocyte nanomotor containing both PEG-b-PCL and PEG-b-PS as a potential candidate for anticancer drug delivery. Well-defined stomatocyte structures could be formed even after incorporation of 50% PEG-b-PCL polymer. Demixing of the two polymers was expected at high percentage of semicrystalline poly(ε-caprolactone) (PCL), resulting in PCL domain formation onto the membrane due to different properties of two polymers. The biodegradable motor system was further shown to move directionally with speeds up to 39 µm/s by converting chemical fuel, hydrogen peroxide, into mechanical motion as well as rapidly delivering the drug to the targeted cancer cell. Uptake by cancer cells and fast doxorubicin drug release was demonstrated during the degradation of the motor system. Such biodegradable nanomotors provide a convenient and efficient platform for the delivery and controlled release of therapeutic drugs.

Self-Guided Supramolecular Cargo-Loaded Nanomotors with Chemotactic Behavior towards Cells.

Delivery vehicles that are able to actively seek and precisely locate targeted tissues using concentration gradients of signaling molecules have hardly been explored. The directed movement toward specific cell types of cargo-loaded polymeric nanomotors along a hydrogen peroxide concentration gradient (chemotaxis) is reported. Through self-assembly, bowl-shaped poly(ethylene glycol)-b-polystyrene nanomotors, or stomatocytes, were formed with platinum nanoparticles entrapped in the cavity while a model drug was encapsulated in the inner compartment. Directional movement of the stomatocytes in the presence of a fuel gradient (chemotaxis) was first demonstrated in both static and dynamic systems using glass channels and a microfluidic flow. The highly efficient response of these motors was subsequently shown by their directional and autonomous movement towards hydrogen peroxide secreting neutrophil cells.

Self-assembly of Janus dendrimers into uniform dendrimersomes and other complex architectures.

Self-assembled nanostructures obtained from natural and synthetic amphiphiles serve as mimics of biological membranes and enable the delivery of drugs, proteins, genes, and imaging agents. Yet the precise molecular arrangements demanded by these functions are difficult to achieve. Libraries of amphiphilic Janus dendrimers, prepared by facile coupling of tailored hydrophilic and hydrophobic branched segments, have been screened by cryogenic transmission electron microscopy, revealing a rich palette of morphologies in water, including vesicles, denoted dendrimersomes, cubosomes, disks, tubular vesicles, and helical ribbons. Dendrimersomes marry the stability and mechanical strength obtainable from polymersomes with the biological function of stabilized phospholipid liposomes, plus superior uniformity of size, ease of formation, and chemical functionalization. This modular synthesis strategy provides access to systematic tuning of molecular structure and of self-assembled architecture.

Predicting the structure of supramolecular dendrimers via the analysis of libraries of AB3 and constitutional isomeric AB2 biphenylpropyl ether self-assembling dendrons.

The synthesis of 4'-hydroxy-4-biphenylpropionic, 3',4'-dihydroxy-4-biphenylpropionic, 3',5'-dihydroxy-4-biphenylpropionic, and 3',4',5'-trihydroxy-4-biphenylpropionic methyl esters via three efficient and modular strategies including one based on Ni-catalyzed borylation and sequential cross-coupling is reported. These building blocks were employed in a convergent iterative approach to the synthesis of one library of 3,4,5-trisubstituted and two libraries of constitutional isomeric 3,4- and 3,5-disubstituted biphenylpropyl ether dendrons. Structural and retrostructural analysis of supramolecular dendrimers revealed that biphenylpropyl ether dendrons self-assemble and self-organize into the same periodic lattices and quasi-periodic arrays observed in previously reported libraries, but with larger dimensions, different mechanisms of self-assembly, and improved solubility, thermal, acidic, and oxidative stability. The different mechanisms of self-assembly led to the discovery of two new supramolecular structures. The first represents a new banana-like lamellar crystal with a four layer repeat. The second is a giant vesicular sphere self-assembled from 770 dendrons that exhibits an ultrahigh molar mass of 1.73 x 10(6) g/mol. Thus, the enhanced size of the self-assembled structures constructed from biphenylpropyl ether dendrons permitted for the first time discrimination of various molecular mechanisms of spherical self-assembly and elaborated a continuum between small filled spheres and very large hollow spheres that is dictated by the primary structure of the dendron. The comparative analysis of libraries of biphenylpropyl ether dendrons with the previously reported libraries of benzyl-, phenylpropyl-, and biphenyl-4-methyl ether dendrons demonstrated biomimetic self-assembly wherein the primary structure of the dendron and to a lesser extent the structure of its repeat unit determines the supramolecular tertiary structure. A "nanoperiodic table" of self-assembling dendrons and supramolecular dendrimers that allows the prediction of the general features of tertiary structures from primary structures was elaborated.