Bladder microenvironment actuated proteomotors with ammonia amplification for enhanced cancer treatment.

Enzyme-driven micro/nanomotors consuming in situ chemical fuels have attracted lots of attention for biomedical applications. However, motor systems composed by organism-derived organics that maximize the therapeutic efficacy of enzymatic products remain challenging. Herein, swimming proteomotors based on biocompatible urease and human serum albumin are constructed for enhanced antitumor therapy via active motion and ammonia amplification. By decomposing urea into carbon dioxide and ammonia, the designed proteomotors are endowed with self-propulsive capability, which leads to improved internalization and enhanced penetration in vitro. As a glutamine synthetase inhibitor, the loaded l-methionine sulfoximine further prevents the conversion of toxic ammonia into non-toxic glutamine in both tumor and stromal cells, resulting in local ammonia amplification. After intravesical instillation, the proteomotors achieve longer bladder retention and thus significantly inhibit the growth of orthotopic bladder tumor in vivo without adverse effects. We envision that the as-developed swimming proteomotors with amplification of the product toxicity may be a potential platform for active cancer treatment.

Hyperthermia-triggered biomimetic bubble nanomachines.

Nanoparticle-based drug delivery systems have gained much attention in the treatment of various malignant tumors during the past decades. However, limited tumor penetration of nanodrugs remains a significant hurdle for effective tumor therapy due to the existing biological barriers of tumoral microenvironment. Inspired by bubble machines, here we report the successful fabrication of biomimetic nanodevices capable of in-situ secreting cell-membrane-derived nanovesicles with smaller sizes under near infrared (NIR) laser irradiation for synergistic photothermal/photodynamic therapy. Porous Au nanocages (AuNC) are loaded with phase transitable perfluorohexane (PFO) and hemoglobin (Hb), followed by oxygen pre-saturation and indocyanine green (ICG) anchored 4T1 tumor cell membrane camouflage. Upon slight laser treatment, the loaded PFO undergoes phase transition due to surface plasmon resonance effect produced by AuNC framework, thus inducing the budding of outer cell membrane coating into small-scale nanovesicles based on the pore size of AuNC. Therefore, the hyperthermia-triggered generation of nanovesicles with smaller size, sufficient oxygen supply and anchored ICG results in enhanced tumor penetration for further self-sufficient oxygen-augmented photodynamic therapy and photothermal therapy. The as-developed biomimetic bubble nanomachines with temperature responsiveness show great promise as a potential nanoplatform for cancer treatment.

Mobile mechanical signal generator for macrophage polarization.

The importance of mechanical signals in regulating the fate of macrophages is gaining increased attention recently. However, the recently used mechanical signals normally rely on the physical characteristics of matrix with non-specificity and instability or mechanical loading devices with uncontrollability and complexity. Herein, we demonstrate the successful fabrication of self-assembled microrobots (SMRs) based on magnetic nanoparticles as local mechanical signal generators for precise macrophage polarization. Under a rotating magnetic field (RMF), the propulsion of SMRs occurs due to the elastic deformation via magnetic force and hydrodynamics. SMRs perform wireless navigation toward the targeted macrophage in a controllable manner and subsequently rotate around the cell for mechanical signal generation. Macrophages are eventually polarized from M0 to anti-inflammatory related M2 phenotypes by blocking the Piezo1-activating protein-1 (AP-1）-CCL2 signaling pathway. The as-developed microrobot system provides a new platform of mechanical signal loading for macrophage polarization, which holds great potential for precise regulation of cell fate.

Light-driven Au-ZnO nanorod motors for enhanced photocatalytic degradation of tetracycline.

The abuse of antibiotics in human medicine and animal husbandry leads to the enrichment of antibiotic residues in aquatic environments, which has been a major problem of environmental pollution over the past decades. Therefore, it is urgent to develop a highly efficient approach to remove antibiotics from aquatic environments. Inspired by the motion characteristics of semiconductor-based micro-/nanomotors, a light-driven Au-ZnO nanomotor system based on vertically aligned ZnO arrays is successfully developed for the enhanced photocatalytic degradation of tetracycline (TC). Under UV light (λ = 365 nm) illumination, these Au-ZnO nanomotors exhibit a high speed in deionized water and TC solution. Due to their efficient motion capability and Au-enhanced charge separation, these light-driven Au-ZnO nanomotors removed almost all TC (40 mg L-1) within 30 min and displayed stable photocatalytic activity for four cycles without any apparent deactivation. The as-developed motor-based strategy for enhanced antibiotic degradation has excellent potential in environmental governance.

Magnetically Actuated Biohybrid Microswimmers for Precise Photothermal Muscle Contraction.

Various strategies have been designed for myotube contraction and skeletal muscle stimulation in recent years, aiming in the field of skeletal muscle tissue engineering and bionics. However, most of the current approaches lack controllability and adaptability for precise stimulation, especially at the microlevel. Herein, wireless and precise activation of muscle by using magnetic biohybrid microswimmers in combination with near-infrared (NIR) laser irradiation is successfully demonstrated. Biohybrid microswimmers are fabricated by dip-coating superparamagnetic Fe3O4 nanoparticles onto the chlorella microalgae, thus endowing robust navigation in various biological media due to magnetic actuation. Under the guidance of a rotating magnetic field, the engineered microswimmer can achieve precise motion toward a single C2C12-derived myotube. Upon NIR irradiation, the photothermal effect from the incorporated Fe3O4 nanoparticles results in local temperature increments of approximately 5 °C in the targeted myotube, which could efficiently trigger the contraction of myotube. The mechanism underlying this phenomenon is a Ca2+-independent case involving direct actin-myosin interactions. In vivo muscle fiber contraction and histological test further demonstrate the effectiveness and biosafety of our design. The as-developed biohybrid microswimmer-based strategy is possible to provide a renovation for tissue engineering and bionics.

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.

MnO2-Based Nanomotors with Active Fenton-like Mn2+ Delivery for Enhanced Chemodynamic Therapy.

Chemodynamic therapy (CDT) is an emerging strategy for cancer treatment based on Fenton chemistry, which can convert endogenous H2O2 into toxic ·OH. However, the limited endocytosis of passive CDT nanoagents with low penetrating capability resulted in unsatisfactory anticancer efficacy. Herein, we propose the successful fabrication of a self-propelled biodegradable nanomotor system based on hollow MnO2 nanoparticles with catalytic activity for active Fenton-like Mn2+ delivery and enhanced CDT. Compared with the passive counterparts, the significantly improved penetration of nanomotors with enhanced diffusion is demonstrated in both the 2D cell culture system and 3D tumor multicellular spheroids. After the intracellular uptake of nanomotors, toxic Fenton-like Mn2+ is massively produced by consuming overexpressed intracellular glutathione (GSH), which has a strong scavenging effect on ·OH, thereby leading to enhanced cancer CDT. The as-developed MnO2-based nanomotor system with enhanced penetration and endogenous GSH scavenging capability shows much promise as a potential platform for cancer treatment in the near future.

Near infrared light activation of an injectable whole-cell cancer vaccine for cancer immunoprophylaxis and immunotherapy.

Cancer vaccines play a key role in the prevention and treatment of early and recurrent tumors. Although they have been widely studied during the past few decades, designing an efficient and economical cancer vaccine is still challenging. Here, we propose an injectable live cell cancer vaccine (InLCCV) using live tumor cells as immunogenic sources for cancer immunoprophylaxis and immunotherapy. InLCCV is fabricated by loading live mouse breast cancer cells (4T1 cells), gold nanorods (GNRs), and super-low-dose lipopolysaccharide (LPS) into a biocompatible Pluronic F127 in situ hydrogel matrix. After in situ inactivation by the photothermal effect of GNRs upon near-infrared (NIR) laser irradiation, immunogenic cell death (ICD) of 4T1 cells is induced and tumor-associated antigens (TAAs) together with loaded LPS are released subsequently. Therefore, dendritic cells and macrophages are activated accordingly, further stimulating the systemic anti-tumor immune response. After vaccinating with InLCCV, the tumor-free percentage of the mice is 60% and the survival rate during the observation period reaches up to 80%. For lung metastasis, the metastatic foci are 3.9-fold less than those of the control group. The as-developed InLCCV shows much promise as a potential platform for breast cancer immunoprophylaxis and immunotherapy.

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.

Bone-Targeting Prodrug Mesoporous Silica-Based Nanoreactor with Reactive Oxygen Species Burst for Enhanced Chemotherapy.

Cancer remains a primary threat to human lives. Recently, amplification of tumor-associated reactive oxygen species (ROS) has been used as a boosting strategy to improve tumor therapy. Here, we report on a bone-targeting prodrug mesoporous silica-based nanoreactor for combined photodynamic therapy (PDT) and enhanced chemotherapy for osteosarcoma. Because of surface modification of a bone-targeting biphosphate moiety and the enhanced permeability and retention effect, the formed nanoreactor shows efficient accumulation in osteosarcoma and exhibits long-term retention in the tumor microenvironment. Upon laser irradiation, the loaded photosensitizer chlorin e6 (Ce6) produces in situ ROS, which not only works for PDT but also functions as a trigger for controlled release of doxorubicin (DOX) and doxycycline (DOXY) from the prodrugs based on a thioketal (TK) linkage. The released DOXY further promotes ROS production, thus perpetuating subsequent DOX/DOXY release and ROS burst. The ROS amplification induces long-term high oxidative stress, which increases the sensitivity of the osteosarcoma to chemotherapy, therefore resulting in enhanced tumor cell inhibition and apoptosis. The as-developed nanoreactor with combined PDT and enhanced chemotherapy based on ROS amplification shows significant promise as a potential platform for cancer treatment.

Hyperthermia-Triggered On-Demand Biomimetic Nanocarriers for Synergetic Photothermal and Chemotherapy.

Nanoparticle-based drug delivery systems with low side effects and enhanced efficacy hold great potential in the treatment of various malignancies, in particular cancer; however, they are still challenging to attain. Herein, an anticancer drug delivery system based on a cisplatin (CDDP) containing nanogel, functionalized with photothermal gold nanorods (GNRs) which are electrostatically decorated with doxorubicin (DOX) is reported. The nanoparticles are formed via the crosslinking reaction of hyaluronic acid with the ancillary anticarcinogen CDDP in the presence of DOX-decorated GNRs. The nanogel is furthermore cloaked with a cancer cell membrane, and the resulting biomimetic nanocarrier (4T1-HANG-GNR-DC) shows efficient accumulation by homologous tumor targeting and possesses long-time retention in the tumor microenvironment. Upon near-infrared (NIR) laser irradiation, in situ photothermal therapy is conducted which further induces hyperthermia-triggered on-demand drug release from the nanogel reservoir to achieve a synergistic photothermal/chemo-therapy. The as-developed biomimetic nanocarriers, with their dual-drug delivery features, homotypic tumor targeting and synergetic photothermal/chemo-therapy, show much promise as a potential platform for cancer treatment.

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.