Multicompartment Tubular Micromotors Toward Enhanced Localized Active Delivery.

A tubular micromotor with spatially resolved compartments is presented toward efficient site-specific cargo delivery, with a back-end zinc (Zn) propellant engine segment and an upfront cargo-loaded gelatin segment further protected by a pH-responsive cap. The multicompartment micromotors display strong gastric-powered propulsion with tunable lifetime depending on the Zn segment length. Such propulsion significantly enhances the motor distribution and retention in the gastric tissues, by pushing and impinging the front-end cargo segment onto the stomach wall. Once the micromotor penetrates the gastric mucosa (pH ≥ 6.0), its pH-responsive cap dissolves, promoting the autonomous localized cargo release. The fabrication process, physicochemical properties, and propulsion behavior are systematically tested and discussed. Using a mouse model, the multicompartment motors, loaded with a model cargo, demonstrate a homogeneous cargo distribution along with approximately four-fold enhanced retention in the gastric lining compared to monocompartment motors, while showing no apparent toxicity. Therapeutic payloads can also be loaded into the pH-responsive cap, in addition to the gelatin-based compartment, leading to concurrent delivery and sequential release of dual cargos toward combinatorial therapy. Overall, this multicompartment micromotor system provides unique features and advantages that will further advance the development of synthetic micromotors for active transport and localized delivery of biomedical cargos.

Active Delivery of VLPs Promotes Anti-Tumor Activity in a Mouse Ovarian Tumor Model.

Virus-like nanoparticles (VLPs) have been used as an attractive means in cancer immunotherapy because of their unique intrinsic immunostimulatory properties. However, for treating metastatic tumors in the peritoneal cavity, such as ovarian cancer, multiple injections of therapy are needed due to the large peritoneal space and fast excretion of therapy. Here, it is reported on the development of active VLP delivery vehicles for the treatment of peritoneal ovarian tumors using biocompatible Qß VLPs-loaded Mg-based micromotors. The autonomous propulsion of such Qß VLPs-loaded Mg-micromotors in the peritoneal fluid enables active delivery of intact immunostimulatory Qß VLPs to the peritoneal space of ovarian tumor bearing mice, greatly enhancing the local distribution and retention of Qß VLPs. Such improved distribution and longer retention time of Qß in the peritoneal cavity leads to enhanced immunostimulation and therefore increased survival rate of tumor-bearing mice compared to a passive Qß treatment. For clinical translation, the active delivery of VLPs holds great promise for tumor immunotherapy toward the treatment of different types of primary and metastatic tumors in the peritoneal cavity.

CdTe Quantum Dots Modified with Cysteamine: A New Efficient Nanosensor for the Determination of Folic Acid.

In this paper, we report the synthesis, characterization, and application of a new fluorescent nanosensor based on water-soluble CdTe quantum dots (QDs) coated with cysteamine (CA) for the determination of folic acid (FA). CdTe/CA QDs were characterized by high-resolution transmission electron microscopy, the zeta potential, and Fourier-transform infrared (FT-IR), UV-visible, and fluorescence spectroscopy. CdTe QDs coated with mercaptopropionic acid (MPA) and glutathione (GSH) were prepared for comparison purposes. The effect of FA on the photoluminescence intensity of the three thiol-capped QDs at pH 8 was studied. Only CdTe/CA QDs showed a notable fluorescence quenching in the presence of FA. Then, a nanosensor based on the fluorescence quenching of the CdTe QDs at pH 8 was explored. Under optimum conditions, the calibration curve showed a linear fluorescence quenching response in a concentration range of FA from 0.16 to 16.4 µM (R2 = 0.9944), with a detection limit of 0.048 µM. A probable mechanism of fluorescence quenching was proposed. The nanosensor showed good selectivity over other possible interferences. This method has been applied for FA quantification in orange beverage samples with excellent results (recoveries from 98.3 to 103.9%). The good selectivity, sensitivity, low cost, and rapidity make CdTe /CA QDs a suitable nanosensor for FA determination.

NIR-Emitting Alloyed CdTeSe QDs and Organic Dye Assemblies: A Nontoxic, Stable, and Efficient FRET System.

In the present work, we synthesize Near Infrared (NIR)-emitting alloyed mercaptopropionic acid (MPA)-capped CdTeSe quantum dots (QDs) in a single-step one-hour process, without the use of an inert atmosphere or any pyrophoric ligands. The quantum dots are water soluble, non-toxic, and highly photostable and have high quantum yields (QYs) up to 84%. The alloyed MPA-capped CdTeSe QDs exhibit a red-shifted emission, whose color can be tuned between visible and NIR regions (608-750 nm) by controlling the Te:Se molar ratio in the precursor mixtures and/or changing the time reaction. The MPA-capped QDs were characterized by UV-visible absorption spectroscopy, fluorescence spectroscopy, transmission electron microscopy (TEM), energy dispersive X-ray spectroscopy (EDS), and zeta potential measurements. Photostability studies were performed by irradiating the QDs with a high-power xenon lamp. The ternary MPA-CdTeSe QDs showed greater photostability than the corresponding binary MPA-CdTe QDs. We report the Förster resonance energy transfer (FRET) from the MPA-capped CdTeSe QDs as energy donors and Cyanine5 NHS-ester (Cy5) dye as an energy acceptor with efficiency (E) up to 95%. The distance between the QDs and dye (r), the Förster distance (R0), and the binding constant (K) are reported. Additionally, cytocompatibility and cell internalization experiments conducted on human cancer cells (HeLa) cells revealed that alloyed MPA-capped CdTeSe QDs are more cytocompatible than MPA-capped CdTe QDs and are capable of ordering homogeneously all over the cytoplasm, which allows their use as potential safe, green donors for biological FRET applications.

Active Intracellular Delivery of a Cas9/sgRNA Complex Using Ultrasound-Propelled Nanomotors.

Direct and rapid intracellular delivery of a functional Cas9/sgRNA complex using ultrasound-powered nanomotors is reported. The Cas9/sgRNA complex is loaded onto the nanomotor surface through a reversible disulfide linkage. A 5 min ultrasound treatment enables the Cas9/sgRNA-loaded nanomotors to directly penetrate through the plasma membrane of GFP-expressing B16F10 cells. The Cas9/sgRNA is released inside the cells to achieve highly effective GFP gene knockout. The acoustic Cas9/sgRNA-loaded nanomotors display more than 80 % GFP knockout within 2 h of cell incubation compared to 30 % knockout using static nanowires. More impressively, the nanomotors enable highly efficient knockout with just 0.6 nm of the Cas9/sgRNA complex. This nanomotor-based intracellular delivery method thus offers an attractive route to overcome physiological barriers for intracellular delivery of functional proteins and RNAs, thus indicating considerable promise for highly efficient therapeutic applications.

Hybrid biomembrane-functionalized nanorobots for concurrent removal of pathogenic bacteria and toxins.

With the rapid advancement of robotic research, it becomes increasingly interesting and important to develop biomimetic micro- or nanorobots that translate biological principles into robotic systems. We report the design, construction, and evaluation of a dual-cell membrane-functionalized nanorobot for multipurpose removal of biological threat agents, particularly concurrent targeting and neutralization of pathogenic bacteria and toxins. Specifically, we demonstrated ultrasound-propelled biomimetic nanorobots consisting of gold nanowires cloaked with a hybrid of red blood cell (RBC) membranes and platelet (PL) membranes. Such hybrid cell membranes have a variety of functional proteins associated with human RBCs and PLs, which give the nanorobots a number of attractive biological capabilities, including adhesion and binding to PL-adhering pathogens (e.g., Staphylococcus aureus bacteria) and neutralization of pore-forming toxins (e.g., α-toxin). In addition, the biomimetic nanorobots displayed rapid and efficient prolonged acoustic propulsion in whole blood, with no apparent biofouling, and mimicked the movement of natural motile cells. This propulsion enhanced the binding and detoxification efficiency of the robots against pathogens and toxins. Overall, coupling these diverse biological functions of hybrid cell membranes with the fuel-free propulsion of the nanorobots resulted in a dynamic robotic system for efficient isolation and simultaneous removal of different biological threats, an important step toward the creation of a broad-spectrum detoxification robotic platform.

Bioinspired Chemical Communication between Synthetic Nanomotors.

While chemical communication plays a key role in diverse natural processes, the intelligent chemical communication between synthetic nanomotors remains unexplored. The design and operation of bioinspired synthetic nanomotors is presented. Chemical communication between nanomotors is possible and has an influence on propulsion behavior. A chemical "message" is sent from a moving activator motor to a nearby activated (receiver) motor by release of Ag+ ions from a Janus polystyrene/Ni/Au/Ag activator motor to the activated Janus SiO2 /Pt nanomotor. The transmitted silver signal is translated rapidly into a dramatic speed change associated with the enhanced catalytic activity of activated motors. Selective and successive activation of multiple nanomotors is achieved by sequential localized chemical communications. The concept of establishing chemical communication between different synthetic nanomotors paves the way to intelligent nanoscale robotic systems that are capable of cooperating with each other.

Author correction: Micromotor-enabled active drug delivery for in vivo treatment of stomach infection.

Marygorret Obonyo, who provided the H. pylori SS1 strain for this work and participated in the design of H. pylori infection studies, was inadvertently omitted from the author list. This has now been corrected in both the PDF and HTML versions of the Article.

Biomedical nanomotors: efficient glucose-mediated insulin release.

We report herein the design of an autonomous glucose-responsive smart nanomachine for insulin (In) delivery based on ultrasound (US)-propelled nanomotors combined with an enzyme-based sensing-effector unit. Gold nanowire (AuNW) motors have been coupled with a mesoporous silica (MS) segment, which was gated with pH-responsive phenylboronic acid (PBA)-glucose oxidase (GOx) supramolecular nanovalves responsible for the insulin release. Glucose-induced protonation of the PBA groups triggers the opening of the pH-driven gate and uncapping of the insulin-loaded nanovalves. The insulin-loaded MS-Au nanomotors displayed an efficient US-driven movement that dramatically accelerates the glucose-triggered insulin release when compared to their static counterparts. Such coupling of the locomotion of nanovehicles with gated insulin-containing nanocontainers and glucose-responsive nanovalves holds great promise for the improved management of diabetes.

Micromotor-enabled active drug delivery for in vivo treatment of stomach infection.

Advances in bioinspired design principles and nanomaterials have led to tremendous progress in autonomously moving synthetic nano/micromotors with diverse functionalities in different environments. However, a significant gap remains in moving nano/micromotors from test tubes to living organisms for treating diseases with high efficacy. Here we present the first, to our knowledge, in vivo therapeutic micromotors application for active drug delivery to treat gastric bacterial infection in a mouse model using clarithromycin as a model antibiotic and Helicobacter pylori infection as a model disease. The propulsion of drug-loaded magnesium micromotors in gastric media enables effective antibiotic delivery, leading to significant bacteria burden reduction in the mouse stomach compared with passive drug carriers, with no apparent toxicity. Moreover, while the drug-loaded micromotors reach similar therapeutic efficacy as the positive control of free drug plus proton pump inhibitor, the micromotors can function without proton pump inhibitors because of their built-in proton depletion function associated with their locomotion.Nano- and micromotors have been demonstrated in vitro for a range of applications. Here the authors demonstrate the in-vivo therapeutic use of micromotors to treat H. pylori infection.

Nanomotor-Enabled pH-Responsive Intracellular Delivery of Caspase-3: Toward Rapid Cell Apoptosis.

Direct and efficient intracellular delivery of enzymes to cytosol holds tremendous therapeutic potential while remaining an unmet technical challenge. Herein, an ultrasound (US)-propelled nanomotor approach and a high-pH-responsive delivery strategy are reported to overcome this challenge using caspase-3 (CASP-3) as a model enzyme. Consisting of a gold nanowire (AuNW) motor with a pH-responsive polymer coating, in which the CASP-3 is loaded, the resulting nanomotor protects the enzyme from release and deactivation prior to reaching an intracellular environment. However, upon entering a cell and exposure to the higher intracellular pH, the polymer coating is dissolved, thereby directly releasing the active CASP-3 enzyme to the cytosol and causing rapid cell apoptosis. In vitro studies using gastric cancer cells as a model cell line demonstrate that such a motion-based active delivery approach leads to remarkably high apoptosis efficiency within a significantly shorter time and with a lower amount of CASP-3 compared to other control groups not involving US-propelled nanomotors. For instance, the reported nanomotor system can achieve 80% apoptosis of human gastric adenocarcinoma cells within only 5 min, which dramatically outperforms other CASP-3 delivery approaches. These results indicate that the US-propelled nanomotors may act as a powerful vehicle for cytosolic delivery of active therapeutic proteins, which would offer an attractive means to enhance the current landscape of intracellular protein delivery and therapy. While CASP-3 is selected as a model protein in this study, the same nanomotor approach can be readily applied to a variety of different therapeutic proteins.

Chitosan-based water-propelled micromotors with strong antibacterial activity.

A rapid and efficient micromotor-based bacteria killing strategy is described. The new antibacterial approach couples the attractive antibacterial properties of chitosan with the efficient water-powered propulsion of magnesium (Mg) micromotors. These Janus micromotors consist of Mg microparticles coated with the biodegradable and biocompatible polymers poly(lactic-co-glycolic acid) (PLGA), alginate (Alg) and chitosan (Chi), with the latter responsible for the antibacterial properties of the micromotor. The distinct speed and efficiency advantages of the new micromotor-based environmentally friendly antibacterial approach have been demonstrated in various control experiments by treating drinking water contaminated with model Escherichia coli (E. coli) bacteria. The new dynamic antibacterial strategy offers dramatic improvements in the antibacterial efficiency, compared to static chitosan-coated microparticles (e.g., 27-fold enhancement), with a 96% killing efficiency within 10 min. Potential real-life applications of these chitosan-based micromotors for environmental remediation have been demonstrated by the efficient treatment of seawater and fresh water samples contaminated with unknown bacteria. Coupling the efficient water-driven propulsion of such biodegradable and biocompatible micromotors with the antibacterial properties of chitosan holds great considerable promise for advanced antimicrobial water treatment operation.