Molybdenum Disulfide‐Based Tubular Microengines: Toward Biomedical Applications

2D molybdenum disulfide (MoS₂) is herein explored as an advanced surface material in the fabrication of powerful tubular microengines. The new catalytic self‐propelled open‐tube bilayer microengines have been fabricated using a template electrodeposition and couple the unique properties of sp² hybridized MoS₂ with highly reactive inner granular Pt catalytic structures. The MoS₂/metal microengines display extremely efficient bubble propulsion, reflecting the granular structure of the inner catalytic platinum or gold layers (compared to the smooth metal surfaces of common micromotors). The efficient movement of functionalized MoS₂ micromotors can address challenges imposed by slow mass transport processes involved in various applications of MoS_2. The delocalized electron network of the MoS₂ outer layer facilitates π–π stacking interactions and endows the tubular microengines with a diverse array of capabilities. These are demonstrated here for efficient loading and release of the drug doxorubicin, and rapid and sensitive “OFF–ON” fluorescent detection of important nucleic acids (miRNA‐21) and proteins (thrombin) using microengines modified with dye‐labeled single‐stranded DNA and aptamer, respectively. Such coupling of the attractive capabilities of 2D‐MoS₂ nanosheets with rapidly moving microengines provides an opportunity to develop multifunctional micromachines for diverse biomedical applications ranging from efficient drug delivery to the detection of important bioanalytes.     

Real‐Time IR Tracking of Single Reflective Micromotors through Scattering Tissues

Medical micromotors have the potential to lead to a paradigm shift in future biomedicine, as they may perform active drug delivery, microsurgery, tissue engineering, or assisted fertilization in a minimally invasive manner. However, the translation to clinical treatment is challenging, as many applications of single or few micromotors require real‐time tracking and control at high spatiotemporal resolution in deep tissue. Although optical techniques are a popular choice for this task, absorption and strong light scattering lead to a pronounced decrease of the signal‐to‐noise ratio with increasing penetration depth. Here, a highly reflective micromotor is introduced which reflects more than tenfold the light intensity of simple gold particles and can be precisely navigated by external magnetic fields. A customized optical IR imaging setup and an image correlation technique are implemented to track single micromotors in real‐time and label‐free underneath phantom and ex vivo mouse skull tissues. As a potential application, the micromotors speed is recorded when moving through different viscous fluids to determine the viscosity of diverse physiological fluids toward remote cardiovascular disease diagnosis. Moreover, the micromotors are loaded with a model drug to demonstrate their cargo‐transport capability. The proposed reflective micromotor is suitable as theranostic tool for sub‐skin or organ‐on‐a‐chip applications.     

Water‐Powered Cell‐Mimicking Janus Micromotor

Cell derivatives have received increasing attention due to their unique ability to mimic many of the natural properties displayed by their source cells. Integration of cell‐derived natural materials with synthetic subjects can be applied toward the development of novel biomedical nano/microscale devices for a wide range of applications, including drug delivery and biodetoxification. Herein, a cell membrane functionalized magnesium‐based Janus micromotor, powered by water, that mimics natural motile cells is reported. The new cell‐mimicking Janus micromotor is constructed by integrating red blood cell (RBC) membranes, gold nanoparticles (AuNPs), and alginate (ALG) onto the exposed surface areas of magnesium microparticles that are partially embedded in Parafilm. The resulting RBC membrane‐coated magnesium (RBC‐Mg) Janus micromotors display an efficient and guided propulsion in water without any external fuel, as well as in biological (albumin‐rich) media with no apparent biofouling, mimicking the movement of natural motile cells. The effective RBC membrane coating bestows the RBC‐Mg Janus micromotors with unique capability for absorbing and neutralizing both biological protein toxins and nerve agent simulants. Such detoxification ability is facilitated greatly by the water‐driven motion of the motors. The RBC‐Mg Janus micromotors represent an exciting progress toward cell‐mimicking microscale motors that hold great promise for diverse biomedical and biodefense applications.     

Multifunctional Visible‐Light Powered Micromotors Based on Semiconducting Sulfur‐ and Nitrogen‐Containing Donor–Acceptor Polymer

Photosensitive micromotors that can be remotely controlled by visible light irradiation demonstrate great potential in biomedical and environmental applications. To date, a vast number of light‐driven micromotors are mainly composed from costly heavy and precious metal‐containing multicomponent systems, that limit the modularity of chemical and physical properties of these materials. Herein, a highly efficient photocatalytic micromotors based exclusively on a purely organic polymer framework—semiconducting sulfur‐ and nitrogen‐containing donor–acceptor polymer, is presented. Thanks to precisely tuned molecular architecture, this material has the ability to absorb visible light due to a conveniently situated energy gap. In addition, the donor‐acceptor dyads within the polymer backbone ensure efficient photoexcited charge separation. Hence, these polymer‐based micromotors can move in aqueous solutions under visible light illumination via a self‐diffusiophoresis mechanism. Moreover, these micromachines can degrade toxic organic pollutants and respond to an increase in acidity of aqueous environments by instantaneous colour change. The combination of autonomous motility and intrinsic fluorescence enables these organic micromotors to be used as colorimetric and optical sensors for monitoring of the environmental aqueous acidity. The current findings open new pathways toward the design of organic polymer‐based micromotors with tuneable band gap architecture for fabrication of self‐propelled microsensors for environmental control and remediation applications.     

Controllable Cellular Micromotors Based on Optical Tweezers

Micromotors hold exciting prospects in biomedical applications but still face a great challenge. To date, there have been few reports of micromotors with high safety, flexible controllability, and full biocompatibility. Here, a multifunctional method based on an optical tweezer system is presented to realize controllable cellular micromotors. The method not only satisfies all of the above criteria but is also independent of the cell types and materials. Optical tweezers are used to generate a dynamic scanning optical trap along a given circular trajectory, which can trap and drive a microparticle or a single cell to move along the trajectory and thus generate a microvortex. Cells within the microvortex will be controllably rotated under an action of shear stress or torque and their rotation rate and direction can be controlled by changing the scanning frequency and direction of the dynamic optical trap. The proposed method is effective for both immotile target cells and swimming target cells. Additionally, it is further applied to realize synchronous translation and rotation of cellular micromotors and to assemble controllable and fully biocompatible cellular micromotor assays. The proposed method is believed to have potential applications in targeted drug delivery, biological microenvironment monitoring and sensing, and biomedical treatment.     

Tumor Microenvironment Responsive Drug‐Dye‐Peptide Nanoassembly for Enhanced Tumor‐Targeting,Penetration, and Photo‐Chemo‐Immunotherapy

Nanomedicine constructed by therapeutics has unique and irreplaceable advantages in biomedical applications, especially in drug delivery for cancer therapy. The strategy, however, used to construct the therapeutics‐based nanomedicines with tumor microenvironmental factor responsiveness is still sophisticated. In this study, an easy‐operating procedure is used to construct a therapeutics‐based nanosystem with active tumor‐targeting, enhanced penetration, and stimuli‐responsive drug release behavior as well as programmed cell death‐1/programmed cell death‐ligand 1 (PD‐1/PD‐L1) blockading mediated immunomodulation to enhance tumor immunotherapy. The matrix metalloproteinase‐2 responsive peptide with the existence of Lyp‐1 sequence contributes to the success of active tumor‐targeting and the enhancement of the penetration of the nanoparticles in tumor tissue. The obtained nanosystem strikingly inhibits the primary tumor growth in the first 24 h (more than 97.5% of tumor cells are inhibited), and total inhibition can be achieved with the combination of photothermal therapy. IR820, which is served as the carrier for the therapeutics, is used as a photosensitizer for photothermal therapy. The progress and aggression of distal tumor has further been alleviated by a d ‐peptide which is an antagonist for PD‐1/PD‐L1 blockage. Therefore, a therapeutics‐constructed multifunctional nanosystem is provided to realize a combinational therapeutic strategy to enhance the therapeutic outcome.     

Red‐Blood‐Cell Waveguide as a Living Biosensor and Micromotor

With great potential in intelligent sensing and actuating systems, biosensors and micromotors are expected to be powerful instruments for early diagnosis and drug delivery in precision medicine. However, it is difficult to ensure the synthetic biosensors and micromotors are compatible with biosystems because of their exogenous building blocks. Biocompatible biosensors and micromotors assembled are reported from living red blood cells (RBCs) optically bound into a waveguide using fiber probes. By monitoring light propagation of the RBC waveguide, the pH of blood solution is detected in real time with an accuracy of 0.05. This can be used for the diagnosis of pH‐related disorders of the blood. After diagnosis, optical torque is exerted on the RBC waveguide, allowing it to rotate as a micromotor and transport microparticles to a target region. The RBC waveguide is then constructed inside zebrafish blood vessels to validate in vivo application. The living biosensors and micromotors are expected to provide a “smart” platform for precise biosensing, medical analysis, and drug delivery.     

3D‐Printed Soft Magnetoelectric Microswimmers for Delivery and Differentiation of Neuron‐Like Cells

Neurodegenerative diseases generally result in irreversible neuronal damage and neuronal death. Cell therapy shows promise as a potential treatment for these diseases. However, the therapeutic targeted delivery of these cells and the in situ provision of a suitable microenvironment for their differentiation into functional neuronal networks remain challenging. A highly integrated multifunctional soft helical microswimmer featuring targeted neuronal cell delivery, on‐demand localized wireless neuronal electrostimulation, and post‐delivery enzymatic degradation is introduced. The helical soft body of the microswimmer is fabricated by two‐photon lithography of the photocurable gelatin–methacryloyl (GelMA)‐based hydrogel. The helical body is then impregnated with composite multiferroic nanoparticles displaying magnetoelectric features (MENPs). While the soft GelMA hydrogel chassis supports the cell growth, and is degraded by enzymes secreted by cells, the MENPs allow for the magnetic transportation of the bioactive chassis, and act as magnetically mediated electrostimulators of neuron‐like cells. The unique combination of the materials makes these microswimmers highly integrated devices that fulfill several requirements for their future translation to clinical applications, such as cargo delivery, cell stimulation, and biodegradability. The authors envision that these devices will inspire new avenues for targeted cell therapies for traumatic injuries and diseases in the central nervous system.     

Wireless Manipulation of Magnetic/Piezoelectric Micromotors for Precise Neural Stem‐Like Cell Stimulation

Precise neural electrical stimulation, which is a means of promoting neuronal regeneration, is a promising solution for patients with neurotrauma and neurodegenerative diseases. In this study, wirelessly controllable targeted motion and precise stimulation at the single‐cell level using S.platensis@Fe₃O₄@tBaTiO₃ micromotors are successfully demonstrated for the first time. A highly versatile and multifunctional biohybrid soft micromotor is fabricated via the integration of S.platensis with magnetic Fe₃O₄ nanoparticles and piezoelectric BaTiO₃ nanoparticles. The results show that this micromotor system can achieve navigation in a highly controllable manner under a low‐strength rotating magnetic field. The as‐developed system can achieve single‐cell targeted motion and then precisely induce the differentiation of the targeted neural stem‐like cell by converting ultrasonic energy to an electrical signal in situ owing to the piezoelectric effect. This new approach toward the high‐precision stimulation of neural stem‐like cells opens up new applications for micromotors and has excellent potential for precise neuronal regenerative therapies.     

Magnetic Helical Microswimmers Functionalized with Lipoplexes for Targeted Gene Delivery

Artificial micro‐/nanoswimmers have various potential applications including minimally invasive diagnosis and targeted therapies, environmental sensing and monitoring, cell manipulation and analysis, and lab‐on‐a‐chip devices. Inspired by natural motile bacteria such as E. Coli, artificial bacterial flagella (ABFs) are one kind of magnetic helical microswimmers. ABFs can perform 3D navigation in a controllable fashion with micrometer precision under low‐strength rotating magnetic fields (<10 mT) and are promising tools for targeted drug delivery in vitro and in vivo. In this work, the successful wirelessly targeted and single‐cell gene delivery to human embryonic kidney (HEK 293) cells using ABFs loaded with plasmid DNA (pDNA) in vitro is demonstrated for the first time. The ABFs are functionalized with lipoplexes containing pDNA to generate functionalized ABFs (f‐ABFs). The f‐ABFs are steered wirelessly by low‐strength rotating magnetic fields and deliver the loaded pDNA into targeted cells. The cells targeted by f‐ABFs are successfully transfected by the transported pDNA and expressed the encoding protein. These f‐ABFs may also be useful for in vivo gene delivery and other applications such as sensors, actuators, cell biology, and lab‐on‐a‐chip environments.     

Multifunctional Silver‐Exchanged Zeolite Micromotors for Catalytic Detoxification of Chemical and Biological Threats

Multifunctional reactive‐zeolite‐based micromotors have been developed and characterized toward effective and rapid elimination of chemical and biological threats. The incorporation of silver ions (Ag⁺) into aluminosilicate zeolite framework imparts several attractive functions, including strong binding to chemical warfare agents (CWA) followed by effective degradation, and enhanced antibacterial activity. The new zeolite‐micromotors protocol thus combines the remarkable adsorption capacity of zeolites and the efficient catalytic properties of the reactive Ag⁺ ions with the autonomous movement of the zeolite micromotors for an accelerated detoxification of CWA. Furthermore, the high antibacterial activity of Ag⁺ along with the rapid micromotor movement enhances the contact between bacteria and reactive Ag⁺, leading to a powerful “on‐the‐fly” bacteria killing capacity. These attractive adsorptive/catalytic features of the self‐propelled zeolite micromotors eliminate secondary environmental contamination compared to adsorptive micromotors. The distinct cubic geometry of the zeolite micromotors leads to enhanced bubble generation and faster movement, in unique movement trajectories, which increases the fluid convection and highly efficient detoxification of CWA and killing of bacteria. The attractive capabilities of these zeolite micromotors will pave the way for their diverse applications in defense, environmental and biomedical applications in more economical and sustainable manner.     

Magnetic Hydrogels and Their Potential Biomedical Applications

Hydrogels find widespread applications in biomedical engineering due to their hydrated environment and tunable properties (e.g., mechanical, chemical, biocompatible) similar to the native extracellular matrix (ECM). However, challenges still exist regarding utilizing hydrogels in applications such as engineering 3D tissue constructs and active targeting in drug delivery, due to the lack of controllability, actuation, and quick‐response properties. Recently, magnetic hydrogels have emerged as a novel biocomposite for their active response properties and extended applications. In this review, the state‐of‐the‐art methods for magnetic hydrogel preparation are presented and their advantages and drawbacks in applications are discussed. The applications of magnetic hydrogels in biomedical engineering are also reviewed, including tissue engineering, drug delivery and release, enzyme immobilization, cancer therapy, and soft actuators. Concluding remarks and perspectives for the future development of magnetic hydrogels are addressed.     

Deciphering,Designing, and Realizing Self‐Folding Biomimetic Microstructures Using a Mass‐Spring Model and Inkjet‐Printed,Self‐Folding Hydrogels

Flat, organic microstructures that can self‐fold into 3D microstructures are promising for tissue regeneration, for being capable of distributing living cells in 3D while forming highly complex, biomimetic architectures to assist cells in performing regeneration. However, the design of self‐folding microstructures is difficult due to a lack of understanding of the underlying formation mechanisms. This study helps bridge this gap by deciphering the dynamics of the self‐folding using a mass‐spring model. This numerical study reveals that self‐folding procedure is multi‐modal, which can become random and unpredictable by involving the interplays between internal stresses, external stimulation, imperfection, and self‐hindrance of the folding body. To verify the numerical results, bilayered, hydrogel‐based micropatterns capable of self‐folding are fabricated using inkjet‐printing and tested. The experimental and numerical results are consistent with each other. The above knowledge is applied to designing and fabricating self‐folding microstructures for tissue‐engineering, which successfully creates 3D, cell‐scaled, and biomimetic microstructures, such as microtubes, branched microtubes, and hollow spheres. Embedded in self‐folded microtubes, human mesenchymal stem cells proliferate and form linear cell‐organization mimicking the cell morphology in muscles and tendons. The above knowledge and study platforms can greatly contribute to the research on self‐folding microstructures and applications to tissue regeneration.     

Dual Stimuli‐Responsive Supramolecular Polypeptide‐Based Hydrogel and Reverse Micellar Hydrogel Mediated by Host–Guest Chemistry

Versatile strategies are currently being discovered for the fabrication of synthetic polypeptide‐based hybrid hydrogels, which have potential applications in polymer therapeutics and regenerative medicine. Herein, a new concept—the reverse micellar hydrogel—is introduced, and a versatile strategy is provided for fabricating supramolecular polypeptide‐based normal micellar hydrogel and reverse micellar hydrogels from the same polypeptide‐based copolymer via the cooperation of host–guest chemistry and hydrogen‐bonding interactions. The supramolecular hydrogels are thoroughly characterized, and a mechanism for their self‐assembly is proposed. These hydrogels can respond to dual stimuli—temperature and pH—and their mechanical and controlled drug‐release properties can be tuned by the copolymer topology and the polypeptide composition. The reverse micellar hydrogel can load 10% of the anticancer drug doxorubicin hydrochloride (DOX) and sustain DOX release for 45 days, indicating that it could be useful as an injectable drug delivery system.     

Remotely Controlled Red Blood Cell Carriers for Cancer Targeting and Near‐Infrared Light‐Triggered Drug Release in Combined Photothermal–Chemotherapy

Red blood cells (RBCs), the “innate carriers” in blood vessels, are gifted with many unique advantages in drug transportation over synthetic drug delivery systems (DDSs). Herein, a tumor angiogenesis targeting, light stimulus‐responsive, RBC‐based DDS is developed by incorporating various functional components within the RBC platform. An albumin bound near‐infrared (NIR) dye, together with a chemotherapy drug doxorubicin, is encapsulated inside RBCs, the surfaces of which are modified with a targeting peptide to allow cancer targeting. Under stimulation by an external NIR laser, the membrane of the RBCs would be destroyed by the light‐induced photothermal heating, resulting in effective drug release. As a proof of principle, RBC‐based cancer cell targeted drug delivery and light‐controlled drug release is demonstrated in vitro, achieving a marked synergistic therapeutic effect through the combined photothermal–chemotherapy. This work presents a novel design of smart RBC carriers, which are inherently biocompatible, promising for targeted combination therapy of cancer.     

Inhibition of Multidrug Resistance of Cancer Cells by Co‐Delivery of DNA Nanostructures and Drugs Using Porous Silicon Nanoparticles@Giant Liposomes

Biocompatible, multifunctional, stimuli responsive, and high drug loading capacity are key factors for the new generation of drug delivery platforms. However, it is extremely challenging to create such a platform that inherits all these advanced properties in a single carrier. Herein, porous silicon nanoparticles (PSi NPs) and giant liposomes are assembled on a microfluidic chip as an advanced nano‐in‐micro platform (PSi NPs@giant liposomes), which can co‐load and co‐deliver hydrophilic and hydrophobic drugs combined with synthesized DNA nanostructures, short gold nanorods, and magnetic nanoparticles. The PSi NPs@giant liposomes with photothermal and magnetic responsiveness show good biocompatibility, high loading capacity, and controllable release. The hydrophilic thermal oxidized PSi NPs encapsulate hydrophobic therapeutics within the hydrophilic core of the giant liposomes, endowing high therapeutics loading capacity with tuneable ratio and controllable release. It is demonstrated that the DAO‐E A DNA nanostructures have synergism with drugs and importantly they contribute to the significant enhancement of cell death to doxorubicin‐resistant MCF‐7/DOX cells, overcoming the multidrug resistance in the cancer cells. Therefore, the PSi NPs@giant liposomes nano‐in‐micro platform hold great potential for a cocktail delivery of drugs and DNA nanostructures for effective cancer therapy, controllable drug release with tuneable therapeutics ratio, and both photothermal and magnetic dual responsiveness.     

Nanoengineering Hybrid Supramolecular Multilayered Biomaterials Using Polysaccharides and Self‐Assembling Peptide Amphiphiles

Developing complex supramolecular biomaterials through highly dynamic and reversible noncovalent interactions has attracted great attention from the scientific community aiming key biomedical and biotechnological applications, including tissue engineering, regenerative medicine, or drug delivery. In this study, the authors report the fabrication of hybrid supramolecular multilayered biomaterials, comprising high‐molecular‐weight biopolymers and oppositely charged low‐molecular‐weight peptide amphiphiles (PAs), through combination of self‐assembly and electrostatically driven layer‐by‐layer (LbL) assembly approach. Alginate, an anionic polysaccharide, is used to trigger the self‐assembling capability of positively charged PA and formation of 1D nanofiber networks. The LbL technology is further used to fabricate supramolecular multilayered biomaterials by repeating the alternate deposition of both molecules. The fabrication process is monitored by quartz crystal microbalance, revealing that both materials can be successfully combined to conceive stable supramolecular systems. The morphological properties of the systems are studied by advanced microscopy techniques, revealing the nanostructured dimensions and 1D nanofibrous network of the assembly formed by the two molecules. Enhanced C2C12 cell adhesion, proliferation, and differentiation are observed on nanostructures having PA as outermost layer. Such supramolecular biomaterials demonstrate to be innovative matrices for cell culture and hold great potential to be used in the near future as promising biomimetic supramolecular nanoplatforms for practical applications.     

Peptide‐Based Nanostructured Materials with Intrinsic Proapoptotic Activities in CXCR4+ Solid Tumors

Protein materials are gaining interest in nanomedicine because of the unique combination of regulatable function and structure. A main application of protein nanoparticles is as vehicles for cell‐targeted drug delivery in the form of nanoconjugates, in which a conventional or innovative drug is associated to a carrier protein. Here, a new nanomedical approach based on self‐assembling protein nanoparticles is developed in which a chemically homogeneous protein material acts, simultaneously, as vehicle and drug. For that, three proapoptotic peptidic factors are engineered to self‐assemble as protein‐only, fully stable nanoparticles that escape renal clearance, for the multivalent display of a CXCR4 ligand and the intracellular delivery into CXCR4⁺ colorectal cancer models. These materials, produced and purified in a single step from bacterial cells, show an excellent biodistribution upon systemic administration and local antitumoral effects. The design and generation of intrinsically therapeutic protein‐based materials offer unexpected opportunities in targeted drug delivery based on fully biocompatible, tailor‐made constructs.     

A Cooperative Dimensional Strategy for Enhanced Nucleus‐Targeted Delivery of Anticancer Drugs

Although previous efforts have focused on altering the size of drug delivery carriers with the goal of improving the efficacy of anticancer therapy, the penetration of nuclear pores still represents a formidable barrier for the existing drug delivery systems. To this end, a cooperative, dimensional strategy is employed that can considerably improve intranuclear drug delivery to augment the overall therapeutic efficacy of therapeutics requiring nuclear entry. This cooperative strategy relies on i) the pH and redox responsiveness of micelles (termed PSPD) to extend blood circulation and increase both the cellular uptake and the redox sensitivity of PSPD to reduce micelles to a size that is more capable of nuclear entry and ii) a dexamethasone‐conjugated micelle (termed Dex‐P₁₂₃) to target nuclei and dilate nuclear pores to allow PSPD to freely penetrate the nuclear pores. The resulting hybrid micelles, termed PSPD/Dex‐P₁₂₃, are found to deliver doxorubicin into cell nuclei more efficiently, thereby inducing more pronounced cytotoxicity against cancer cells in vitro. Importantly, a much more effective inhibition of tumor growth is observed in tumor‐bearing mice, demonstrating the feasibility of this cooperative strategy for in vivo applications. The current study defines a useful dimensional strategy to improve nuclear‐targeted and intranuclear drug delivery.     

A Hybrid Carrier System Based on Origami Nanostrucutures and Layer‐by‐Layer Microparticles

Recent progress in DNA nanotechnology allows the fabrication of 3D structures that can be loaded with a large variety of molecular cargos and even be responsive to external stimuli. This makes the use of DNA nanostructures a promising approach for applications in nanomedicine and drug delivery. However, their low stability in the extra‐ and intracellular environment as well as low cellular uptake rates and release rates from endosomes into the cytoplasm hamper the efficient and targeted use of DNA nanostructures in medical applications. Here, such major obstacles are overcome by integrating DNA origami nanostructures into superordinated layer‐by‐layer based microparticles made from biopolymers. The modular assembly of the polymer layer allows a high‐density incorporation of the DNA structures at different depth. This enables controllable protection of the DNA nanostructures over extended durations in a broad range of extra‐ and intracellular conditions without compromising the cell viability. Furthermore, by producing protein‐complexed DNA nanostructures it is demonstrated that molecular cargo can be conveniently integrated into the developed hybrid system. This work provides the basis for a new multistage carrier system allowing for an efficient and protected transport of active agents inside responsive DNA nanostructures.