Bottle Nanomotors Amplify Tumor Oxidative Stress for Enhanced Calcium Overload/Chemodynamic Therapy.

Developing multifunctional, stimuli-responsive nanomedicine is intriguing because it has the potential to effectively treat cancer. Yet, poor tumor penetration of nanodrugs results in limited antitumor efficacy. Herein, an oxygen-driven silicon-based nanomotor (Si-motor) loaded with MnO and CaO2 nanoparticles is developed, which can move in tumor microenvironment (TME) by the cascade reaction of CaO2 and MnO. Under acidic TME, CaO2 reacts with acid to release Ca2+ to induce mitochondrial damage and simultaneously produces O2 and H2O2, when the loaded MnO exerts Fenton-like activity to produce ·OH and O2 based on the produced H2O2. The generated O2 drives Si-motor forward, thus endowing active delivery capability of the formed motors in TME. Meanwhile, MnO with glutathione (GSH) depletion ability further prevents reactive oxygen species (ROS) from being destroyed. Such TME actuated Si-motor with enhanced cellular uptake and deep penetration provides amplification of synergistic oxidative stresscaused by intracellular Ca2 + overloading, GSH depletion induced by Mn2+, and Mn2+ mediated chemodynamic treatment (CDT), leading to excellent tumor cell death. The created nanomotor may offer an effective platform for active synergistic cancer treatment.

NIR-II Light-Actuated Nanomotors for Enhanced Photoimmunotherapy Toward Hepatocellular Carcinoma.

Light-propelled nanomotors, which can convert external light into mechanical motion, have shown considerable potential in the construction of a new generation of drug delivery systems. However, the therapeutic efficacy of light-driven nanomotors is always unsatisfactory due to the limited penetration depth of near-infrared-I (NIR-I) light and the inherent biocompatibility of the motor itself. Herein, an asymmetric nanomotor (Pd@ZIF-8/R848@M JNMs) with efficient motion capability is successfully constructed for enhanced photoimmunotherapy toward hepatocellular carcinoma. Under near-infrared-II (NIR-II) irradiation, Pd@ZIF-8/R848@M JNMs convert light energy into heat energy, exhibiting self-thermophoretic locomotion to penetrate deeper into tumor tissues to achieve photothermal therapy. At the same time, functionalized with an immune-activated agent Resiquimod (R848), our nanomotors could convert a "cold tumor" into a "hot tumor", transforming the immunosuppressive microenvironment into an immune-activated state, thus achieving immunotherapy. Dual photoimmunotherapy of the as-developed NIR-II light-driven Pd@ZIF-8/R848@M JNMs demonstrates considerable tumor inhibition effects, offering a promising therapeutic approach in the field of anticancer therapy.

Light-Driven Biomimetic Nanomotors for Enhanced Photothermal Therapy.

Nanotechnology-based strategy has recently drawn extensive attention for the therapy of malignant tumors due to its distinct strengths in cancer diagnosis and treatment. However, the limited intratumoral permeability of nanoparticles is a major hurdle to achieving the desired effect of cancer treatment. Due to their superior cargo towing and reliable penetrating property, micro-/nanomotors (MNMs) are considered as one of the most potential candidates for the coming generation of drug delivery platforms. Here, near-infrared (NIR)-actuated biomimetic nanomotors (4T1-JPGSs-IND) are fabricated successfully and we demonstrate that 4T1-JPGSs-IND selectively accumulate in homologous tumor regions due to the effective homing ability. Upon laser irradiation, hyperthermia generated by 4T1-JPGSs-IND leads to self-thermophoretic motion and photothermal therapy (PTT) to ablate tumors with a deep depth, thereby improving the photothermal therapeutic effect for cancer management. The developed nanomotor system with multifunctionalities exhibits promising potential in biomedical applications to fight against various diseases.

A NIR-driven green affording-oxygen microrobot for targeted photodynamic therapy of tumors.

Photodynamic therapy (PDT) is a light-activated local treatment modality that has promising potential in cancer therapy. However, ineffective delivery of photosensitizers and hypoxia in the tumor microenvironment severely restrict the therapeutic efficacy of PDT. Herein, phototactic Chlorella (C) is utilized to carry photosensitizer-encapsulated nanoparticles to develop a near-infrared (NIR) driven green affording-oxygen microrobot system (CurNPs-C) for enhanced PDT. Photosensitizer (curcumin, Cur) loaded nanoparticles are first synthesized and then covalently attached to C through amide bonds. An in vitro study demonstrates that the developed CurNPs-C exhibits continuous oxygen generation and desirable phototaxis under NIR treatment. After intravenous injection, the initial 660 nm laser irradiation successfully induces the active migration of CurNPs-C to tumor sites for higher accumulation. Upon the second 660 nm laser treatment, CurNPs-C produces abundant oxygen, which in turn induces the natural product Cur to generate more reactive oxygen species (ROS) that significantly inhibit the growth of tumors in 4T1 tumor-bearing mice. This contribution showcases the ability of a light-driven green affording-oxygen microrobot to exhibit targeting capacity and O2 generation for enhancing photodynamic therapy.

Micromotor-Enabled Active Hydrogen and Tobramycin Delivery for Synergistic Sepsis Therapy.

Sepsis is a highly heterogeneous syndrome normally characterized by bacterial infection and dysregulated systemic inflammatory response that leads to multiple organ failure and death. Single anti-inflammation or anti-infection treatment exhibits limited survival benefit for severe cases. Here a biodegradable tobramycin-loaded magnesium micromotor (Mg-Tob motor) is successfully developed as a potential hydrogen generator and active antibiotic deliverer for synergistic therapy of sepsis. The peritoneal fluid of septic mouse provides an applicable space for Mg-water reaction. Hydrogen generated sustainably and controllably from the motor interface propels the motion to achieve active drug delivery along with attenuating hyperinflammation. The developed Mg-Tob motor demonstrates efficient protection from anti-inflammatory and antibacterial activity both in vitro and in vivo. Importantly, it prevents multiple organ failure and significantly improves the survival rate up to 87.5% in a high-grade sepsis model with no survival, whereas only about half of mice survive with the individual therapies. This micromotor displays the superior therapeutic effect of synergistic hydrogen-chemical therapy against sepsis, thus holding great promise to be an innovative and translational drug delivery system to treat sepsis or other inflammation-related diseases in the near future.

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.

Influence of partial cement substitution by ground blast furnace slag on the mechanical properties of phosphogypsum cemented backfill.

Phosphogypsum (PG) stockpiles occupied a large amount of land resources, and serious environmental pollution problems have attracted the attention of countries around the world. Cemented backfill can reduce the environmental problems caused by tailings stockpiles and is an important development trend in green mine construction. To investigate the effect of binder type on the performance of PG cemented backfill, this paper used ground granulated blast furnace slag (GGBFS) to substitute part of Portland cement (PC) as binder and studied the effect of different ratios of binder on the uniaxial compressive strength (UCS), surface crack extension, acoustic emission (AE) characteristics, and microstructure of PG cemented backfill. The results show that substituting part of PC with GGBFS is beneficial to improve the mechanical properties of PG cemented backfill. When PC was substituted by 50% of GGBFS, the 28d UCS of the backfill was increased from 1.535 to 4.539 MPa. Furthermore, the UCS of the backfill gradually increased as the GGBFS substitution level increased, and more AE signals could be monitored during uniaxial compression. Compared with PC, the sulfate in PG participates in the hydration reaction of GGBFS, more hydrated calcium-aluminum-silicate-hydrate (C-A-S-H) gels and ettringite (AFt) are formed, and the microstructure of the backfill is denser, and the required strength can be obtained with less binder. Thus, substituting part PC with GGBFS as a binder can provide an economical and environmentally friendly alternative for the consumption and reuse of large quantities of PG.

Study on mechanical properties and damage characteristics of cemented waste rock-tailing backfill.

Tailing and waste rock-cemented filling is an effective way to solve the problem solid waste in mines. In this paper, the effects of waste rock content and cement-sand ratio on the properties of tailing-waste rock-cemented filling materials and cemented backfill were analyzed based on the single-factor multi-level experimental design method. The results show that with the increase of waste rock content, the fluidity of the filling slurry increases first and then decreases, the bleeding rate increased gradually, and the compressive strength of the backfill increases first and then decreases. When the waste rock content is 60% and the cement-sand ratio is 1:4, the cemented backfill has higher compressive strength. With the increase of waste rock content, the interface failure area between waste rock particles and cementitious matrix under loading gradually increases, the crack extension is more complex, and the acoustic emission (AE) ringing count is higher. Microstructural analysis showed that the main hydration products in the cemented backfill were calcium silicate hydrated (C-S-H) gels, ettringite (AFt), and calcium hydroxide (Ca(OH)2). Because there is more content of hydration products, the microstructure of the cemented backfill was denser and the compressive strength was higher. Based on the results of uniaxial compression tests, the damage constitutive model of cemented backfill with different waste rock contents and cement-sand ratios was established, which could provide guidance for the design and safety production of phosphate rock filling engineering.

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.

Self-Propelled Proteomotors with Active Cell-Free mtDNA Clearance for Enhanced Therapy of Sepsis-Associated Acute Lung Injury.

Acute lung injury (ALI) is a frequent and serious complication of sepsis with limited therapeutic options. Gaining insights into the inflammatory dysregulation that causes sepsis-associated ALI can help develop new therapeutic strategies. Herein, the crucial role of cell-free mitochondrial DNA (cf-mtDNA) in the regulation of alveolar macrophage activation during sepsis-associated ALI is identified. Most importantly, a biocompatible hybrid protein nanomotor (NM) composed of recombinant deoxyribonuclease I (DNase-I) and human serum albumin (HSA) via glutaraldehyde-mediated crosslinking is prepared to obtain an inhalable nanotherapeutic platform targeting pulmonary cf-mtDNA clearance. The synthesized DNase-I/HSA NMs are endowed with self-propulsive capability and demonstrate superior performances in stability, DNA hydrolysis, and biosafety. Pulmonary delivery of DNase-I/HSA NMs effectively eliminates cf-mtDNAs in the lungs, and also improves sepsis survival by attenuating pulmonary inflammation and lung injury. Therefore, pulmonary cf-mtDNA clearance strategy using DNase-I/HSA NMs is considered to be an attractive approach for sepsis-associated ALI.

Nanorobot-Mediated Synchronized Neuron Activation.

Interactions between active materials lead to collective behavior and even intelligence beyond the capability of individuals. Such behaviors are prevalent in nature and can be observed in animal colonies, providing these species with diverse capacities for communication and cooperation. In artificial systems, however, collective intelligence systems interacting with biological entities remains unexplored. Herein, we describe black (B)-TiO2@N/Au nanorobots interacting through photocatalytic pure water splitting-induced electrophoresis that exhibit periodic swarming oscillations under programmed near-infrared light. The periodic chemical-electric field generated by the oscillating B-TiO2@N/Au nanorobot swarm leads to local neuron activation in vitro. The field oscillations and neurotransmission from synchronized neurons further trigger the resonance oscillation of neuron populations without synaptic contact (about 2 mm spacing), in different ways from normal neuron oscillation requiring direct contact. We envision that the oscillating nanorobot swarm platforms will shed light on contactless communication of neurons and offer tools to explore interactions between neurons.

Leaching toxicity and deformation failure characteristics of phosphogypsum-based cemented paste backfill under chemical solution erosion.

In order to explore the potential environmental and safety risks of phosphogypsum-based cemented paste backfill (PCPB) in mines, aiming at the actual problems of different acidity and alkalinity of the groundwater environment where PCPB is located, the chemical solution erosion test, element concentration determination test, uniaxial compressive strength (UCS) test, and microscopic analysis test of PCPB were carried out. The effects of three different chemical solutions, HCl solution, NaOH solution, and pure water on the leaching toxicity and deformation failure characteristics of PCPB were analyzed. The kinetic equations of pH value of PCPB in the HCl and NaOH solutions, the leaching models of total P and fluoride, and the UCS erosion model of PCPB were established. The research shows that the pH value of PCPB is weak alkaline or alkalinity, when it reaches dynamic equilibrium in different chemical solutions. The leaching concentration of total P is higher than the Class III standard of surface water; the leaching concentration of fluoride is higher than the Class III standard of surface water, the Class III standard of groundwater, and the Class I standard of sewage. In the early stage of chemical solution erosion, scanning electron microscope (SEM) images show that the hydration product C-S-H gel and Aft are intertwined and firmly combined. The research results have important engineering practice and application value in mine environmental governance and safety management.

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.

Magnetically Actuated Biodegradable Nanorobots for Active Immunotherapy.

An efficient and cost-effective therapeutic vaccine is highly desirable for the prevention and treatment of cancer, which helps to strengthen the immune system and activate the T cell immune response. However, initiating such an adaptive immune response efficiently remains challenging, especially the deficient antigen presentation by dendritic cells (DCs) in the immunosuppressive tumor microenvironment. Herein, an efficient and dynamic antigen delivery system based on the magnetically actuated OVA-CaCO3 -SPIO robots (OCS-robots) is rationally designed for active immunotherapy. Taking advantage of the unique dynamic features, the developed OCS-robots achieve controllable motion capability under the rotating magnetic field. Specifically, with the active motion, the acid-responsiveness of OCS-robots is beneficial for the tumor acidity attenuating and lysosome escape as well as the subsequent antigen cross-presentation of DCs. Furthermore, the dynamic OCS-robots boost the crosstalk between the DCs and antigens, which displays prominent tumor immunotherapy effect on melanoma through cytotoxic T lymphocytes (CTLs). Such a strategy of dynamic vaccine delivery system enables the active activation of immune system based on the magnetically actuated OCS-robots, which presents a plausible paradigm for incredibly efficient cancer immunotherapy by designing multifunctional and novel robot platforms in the future.

Dip effect of asymmetric deformation characteristics for stope roof-pillar system.

In underground mining, the dip angle is one of the widely recognized factors that cause the asymmetric deformation of the goaf/stope roof, but characterizing the degree of asymmetric roof deformation is still a challenge. The goal of this research is to try to solve this problem with a theoretical model and numerical method. In an inclined ore seam, the mining load produces both normal and tangential effects on the inclined roof. A theoretical model was developed employing thin plate theory for enabling describe the asymmetric deformation of the roof caused by inclination. The proposed model describes not only the bending deformation state of the roof but also the deformation characteristics. Subsequently, the law of asymmetric deformation of roofs with varying inclinations was presented by numerical method. Under the same conditions, the numerical results of the asymmetric deformation of the roof are consistent with the theoretical results. Finally, the degree of asymmetrical deformation was characterized and quantified by the distance between the maximum subsidence point and the center of the roof. There exist three modes of asymmetric deformation, which are controlled by both dip angle and in-situ stress ratio. The results show that the shear load caused by dip angle is the root cause of asymmetric deformation of the roof. This study provides a theoretical basis for the asymmetric deformation control of the inclined roof.

Real-Time Micromotor Probe for Immune Neutrophil Activation State.

Neutrophil activation is a hallmark of the immune response. Approaches to identify neutrophil activation in real time are necessary but are still lacking. In this study, magnetic Spirulina micromotors are used as label-free probes that exhibit differences in motility under different neutrophil activation states. This is correlated with different secretions into the extracellular environment by activated/non-activated cells and local environmental viscoelasticity. The micromotor platform can bypass non-activated immune cells while being stopped by activated cells. Thus, the micromotors can serve as label-free biomechanical probes of the immune cell state. They can detect the activation state of target immune cells in real time and with single-cell precision, which provides new ideas for the diagnosis and treatment of diseases while deepening understanding of the biomechanics of activated immune cells.

Application of Microscopic Highly Hydrophilic Silica-Based Nanocomposites with High Surface Exposure in the Efficient Identification of Intact N-Glycopeptides.

Glycosylation of proteins regulates the life activities of organisms, while abnormalities of glycosylation sites and glycan structures occur in various serious diseases such as cancer. A separation and enrichment procedure is necessary to realize the analysis of the glycoproteins/peptides by mass spectrometry, for which the surface hydrophilicity of the material is an important factor for the separation and enrichment performance. In the present work, under the premise of an obvious increase of the surface silicon exposure (79.6%), the amount of surface polar silanol is remarkably generated accompanying the introduction of the active amino groups on the surface of silica. The microscopic hydrophilicity, which is determined with water physical-adsorption measurements and can directly reflect the interaction of water molecules and the intrinsic surface of the material, maximally increases by 44%. This microscopically highly hydrophilic material shows excellent enrichment ability for glycopeptides, such as extremely low detection limits (0.01 fmol µL-1), remarkable selectivity (1:8000), and size exclusion effects (1:8000). A total of 677 quantifiable intact N-glycopeptides were identified from the serum of patients with cervical cancer, and the glycosylation site and glycan structure were analyzed in depth, indicating that this novel material can show a broad practical application in cervical cancer diagnosis.

Mechanical properties and damage constitutive model of phosphogypsum-based cemented backfill under hydrochemical action.

In order to analyze the early mechanical properties and damage characteristics of phosphogypsum-based cemented backfill (PCB) under hydrochemical action, hydrochemical erosion and uniaxial compression strength (UCS) tests were carried out with HCl solution, NaOH solution, and water respectively. The damage degree is defined by taking the effective bearing area of the soluble cements of PCB under hydrochemistry action as the chemical damage variable, and the modified damage parameter α, which reflects the damage development characteristics, is introduced to construct the damage constitutive model of PCB considering chemical damage and load damage, and the theoretical model is verified with the experimental results. The results show that the damage constitutive model curves of PCB under different hydrochemical action are in good agreement with the experimental results, which verifies the correctness of the theoretical model. When the modified damage parameter α decreases from 1.0 to 0.8, the residual load-bearing capacity of PCB gradually increases, with the damage values of PCB samples in HCl solution and water gradually increasing before the peak and decreasing after the peak, while the damage values of PCB samples in NaOH solution show an overall increasing trend before and after the peak. The slope of the post peak curve of PCB decreases with increasing model parameter n. The results of the study can provide theoretical support and practical guidance for the strength design, long-term erosion deformation, and prediction of PCB in hydrochemical environment.

Immunostimulant In Situ Fibrin Gel for Post-operative Glioblastoma Treatment by Macrophage Reprogramming and Photo-Chemo-Immunotherapy.

Tumor recurrence remains the leading cause of treatment failure following surgical resection of glioblastoma (GBM). M2-like tumor-associated macrophages (TAMs) infiltrating the tumor tissue promote tumor progression and seriously impair the efficacy of chemotherapy and immunotherapy. In addition, designing drugs capable of crossing the blood-brain barrier and eliciting the applicable organic response is an ambitious challenge. Here, we propose an injectable nanoparticle-hydrogel system that uses doxorubicin (DOX)-loaded mesoporous polydopamine (MPDA) nanoparticles encapsulated in M1 macrophage-derived nanovesicles (M1NVs) as effectors and fibrin hydrogels as in situ delivery vehicles. In vivo fluorescence imaging shows that the hydrogel system triggers photo-chemo-immunotherapy to destroy remaining tumor cells when delivered to the tumor cavity of a model of subtotal GBM resection. Concomitantly, the result of flow cytometry indicated that M1NVs comprehensively improved the immune microenvironment by reprogramming M2-like TAMs to M1-like TAMs. This hydrogel system combined with a near-infrared laser effectively promoted the continuous infiltration of T cells, restored T cell effector function, inhibited the infiltration of myeloid-derived suppressor cells and regulatory T cells, and thereby exhibited a strong antitumor immune response and significantly inhibited tumor growth. Hence, MPDA-DOX-NVs@Gel (MD-NVs@Gel) presents a unique clinical strategy for the treatment of GBM recurrence.

Arthritic Microenvironment Actuated Nanomotors for Active Rheumatoid Arthritis Therapy.

Increasing O2 demand and excessive ROS production are the main features of arthritic microenvironment in rheumatoid arthritis (RA) joints and further play pivotal roles in inflammation exacerbation. In this work, a system of in situ regulation of arthritic microenvironment based on nanomotor strategy is proposed for active RA therapy. The synthesized MnO2 -motors enable catalytic regulation of RA microenvironment by consuming the overproduced H2 O2 and generating O2 synergistically. The generated O2 under H2 O2 -rich conditions functions as inflammation detector, propellant for enhanced diffusion, as well as ameliorator for the hypoxic synovial microenvironment. Owing to O2 generation and inflammation scavenging, the MnO2 -motors block the re-polarization of pro-inflammatory macrophages, which results in significantly decreased secretion of multiple pro-inflammatory cytokines both in vitro and in vivo. In addition, intra-articular administration of MnO2 -motors to collagen-induced arthritis rats (CIA rats) effectively alleviates hypoxia, synovial inflammation, bone erosion, and cartilage degradation in joints. Therefore, the proposed arthritic regulation strategy shows great potential to seamlessly integrate basic research of RA with clinical translation.