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Taste is one of the basic senses of living organisms and can recognize sour, bitter, salty, sweet and umami tastes. Bitter taste receptor is a class of G protein-coupled receptors capable of sensing bitterness. Initially, bitter taste receptor was thought to be only found in the taste buds of the tongue, palate and throat. Recent research has shown that in addition to the oral cavity, the bitter taste receptor is also present in the intestinal tract, respiratory tract, urinary tract, vascular smooth muscle, nervous system, thyroid gland and other tissues and organs to regulate body homeostasis and resist disorders . In this review, we focus on the effects of the bitter taste receptor outside the oral cavity to lay the groundwork for future research.

This article proposes a piezoelectric-driven insect-scale soft robot with ring-like curved legs, enabling it to traverse complex three-dimensional (3D) terrain only by body-terrain mechanical action. Relying on the repeated deformation of the main body's n and u shapes, the robot's leg-ground mechanical action produces an "elastic gait" to move. Regarding the detailed design, first, a theoretical curve of the front leg with a fixed angle of attack of 75° is designed by finite element simulation and comparative experiments. It ensures no increase in drag and no decrease in the lift when climbing steps. Second, a ring-like leg structure with 100% closed degree is proposed to ensure a smooth pass through small-sized uneven terrain without getting stuck. Then, the design of the overall asymmetrical structure of the robot can improve the conversion ratio of vibration to forward force. The shape of curved legs is controlled by pulling the flexible leg structure with two metal wires working as spokes. The semirigid leg structure made of fully flexible materials has shape stability and structural robustness. Compared with the plane-legged robot, the curved-legged robot can smoothly traverse different rugged 3D terrains and cross the terrain covering obstacles 0.36 times body height (BH) at a speed of4 body lengths per second. Moreover, the curved-legged robot shows 100% and 64% chances of climbing steps with 1.2- and 1.9-times BH, respectively.

Cancer immunotherapy has been a favorable strategy for facilitating antitumor immunity. However, immune tolerance and an ultimate immunosuppressive tumor microenvironment (ITM) are primary obstacles. To achieve the goals of remodeling the ITM and promoting cancer immunotherapy, a versatile nanoparticle codelivering shikonin (SK) and PD-L1 knockdown siRNA (SK/siR-NPs) was reported. SK/siR-NPs are demonstrated to tellingly induce the immunogenic cell death (ICD) of tumor cells, leading to increased dendritic cell maturation. Moreover, SK/siR-NPs can cause an efficacious inhibition of PD-L1, leading to enhanced cytotoxic T lymphocyte response to tumor cells. Most importantly, SK/siR-NPs can restrain lactate production via the downregulation of pyruvate kinase-M2 (PKM2) and eventually repolarize tumor associated macrophages (TAMs) from the M2-subtype to M1-subtype states. Meanwhile, SK/siR-NPs suppress regulatory T lymphocytes to fight with the ITM. Overall, the developed co-delivery system presents a significant potential for cancer immunotherapy through simultaneously inducing ICD, repolarizing M2-TAMs, and relieving PD-L1 pathway-regulated immune tolerance.

A time- and cost-effective fabrication methodology via a two-mode mechanical cutting process for multilayer stretchable electronics has been developed without using the conventional photolithography-based processes. A commercially available vinyl cutter is used for defining complex patterns on designated material layers by adjusting the applied force and the depth of the cutting blade. Two distinct modes of mechanical cutting can be achieved and employed to establish the basic fabrication procedures for common features in stretchable electronics, such as the metal interconnects, contact pads, and openings by the "tunnel cut" mode, and the flexible overall structure by the "through cut" mode. Three robust and resilient stretchable systems have been demonstrated, including a water-resistant, omnidirectionally stretchable supercapacitor array, a stretchable mesh applicable in sweat extraction and sensing, and a skin-mountable human breathing monitoring patch. Results show excellent electronic performances of these devices made of multilayer functional materials after repetitive large deformations.

Chlorambucil (CLB) is widely used in the treatment of solid tumors. However, CLB has poor water solubility, short half-life and side effects such as leucopenia and thrombocytopenia, in addition to the inhibition of tumor immune microenvironment. In our study, chlorambucil-chitosan (CLB-CS) prodrug micelles were successfully prepared, and glycyrrhetinic acid (GA) was selected, which could improve the immunosuppressive microenvironment and actively targeted liver cancer cells. At the tumor site, CLB blocked the cell cycle and promoted apoptosis. In addition, GA improved the tumor microenvironment by increasing the proportion of CD4

Background Carbon dots (CDs) have attracted extensive attention in recent years because of their high biocompatibility and unique optical property. But they could not be well applied in the drug delivery system to enable distribution in tumor sites with their low pH sensitivity. They are barriers for drug delivery. CDs as an imaging proper were conjugated with doxorubicin (DOX) lipid-coated calcium phosphate (LCP) nanoparticle, for a pH-sensitive nanocarrier and delivery of the antitumor drugs. Materials and methods CDs were prepared by one-step hydrothermal treatment of citric acid and ethylenediamine. The nanoparticles were simply prepared by using microemulsion technology to form calcium phosphate (CaP) core and further coated with cationic lipids. Results The structure was characterized by FTIR, XRD and TEM. In vitro release study revealed that DOX-CDs@LCP was pH dependent. The cytotoxicity assay demonstrated that it exhibited enhanced efficiency compared to the control group (DOX-CDs), but weaker than free DOX. The cellular uptake revealed that these pH-sensitive nanoparticles could be taken up effectively and deliver DOX into the cytoplasm to reach antitumor effect. The fluorescence imaging indicated that DOX-CDs@LCP mostly distributed in the tumor region due to the enhanced permeability and retention effect (EPR) to reduce its systematical toxicity. Importantly, an antitumor activity study demonstrated that the DOX-CDs@LCP nanoparticles had higher antitumor activity than any other groups and lower toxicity. The results showed that LCP could significantly promote the release in tumor microenvironment due to pH-response. The DOX-CDs could enhance load capacity and reduce drug premature releasing; real-time tracking of efficacy as confocal imaging contrast agent. Thus, DOX-CDs@LCP had antitumor capacity and lower systematic toxicity in tumor therapy. Conclusion DOX-CDs@LCP were proven as a promising tumor pH-sensitive and imaging-guided drug delivery system for liver cancer chemotherapy.

Exosomes are naturally secreted nanovesicles that have emerged as a promising therapeutic nanodelivery platform, due to their specific composition and biological properties. However, challenges like considerable complexity, low isolation yield, drug payload, and potential safety concerns substantially reduce their pharmaceutical acceptability. Given that the nano-bio-interface is a crucial factor for nanocarrier behavior and function, modification of synthetic nanoparticles with the intrinsic hallmarks of exosomes' membrane to create exosome mimetics could allow for siRNA delivery in a safer and more efficient manner. Herein, connexin 43 (Cx43)-embedded, exosome-mimicking lipid bilayers coated chitosan nanoparticles (Cx43/L/CS NPs) were constructed by using cell-free (CF) synthesis systems with plasmids encoding Cx43 in the presence of lipid-coated CS NPs (L/CS NPs). The integration of de novo synthesized Cx43 into the lipid bilayers of L/CS NPs occurred cotranslationally during one-pot reaction and, more importantly, the integrated Cx43 was functionally active in transport. In addition to considerably lower cytotoxicity (

Doxorubicin is a commonly-used anticancer drug, which has disadvantages such as drug resistance and side effects. Combination therapy is considered to be an effective strategy to overcome these problems. According to the previous studies, Lovastatin could enhance the antitumor activity, reverse drug resistance and reduce associated toxicity of Doxorubicin. In this study, Doxorubicin-Lovastatin-liposomes were prepared successfully. The optimized composition of Doxorubicin-Lovastatin-liposomes were selected using Box-Behnken design. Doxorubicin-Lovastatin-liposomes were demonstrated to have uniform particle size, high encapsulation efficiency and great release behavior in vitro. Biodistribution studies proved that the liposomes displayed great tumor accumulation and targeting. Meanwhile, pharmacokinetic studies showed that Lovastatin could effectively improve the bioavailability of Doxorubicin and slow down the elimination rate in vivo. Furthermore, according to the results in vivo, Doxorubicin-Lovastatin-liposomes could efficiently inhibit the growth of tumor and reduce pathological damages to the main tissues comparing with the single drug group. In conclusion, Doxorubicin-Lovastatin-liposomes might be a promising method of treating liver cancer.

Disulfiram loaded biotin-polyethylene glycol 2000- distearyl phosphatidyl ethanolamine modified nanostructured lipid carriers were generated so as to increase the long-circulation time, enhance encapsulation efficiency, loading capacity and improve targeting ability. The optimized composition of disulfiram loaded biotin-polyethylene glycol 2000- distearyl phosphatidyl ethanolamine modified nanostructured lipid carriers was selected using central composite design, showing a spherical shape of 103 ± 3 nm in particle size as well as loading capacity of 4.72 ± 0.89 and encapsulation efficiency of 89.87 ± 0.42. The noncrystalline state of disulfiram was recognized by differential scanning calorimetry. The in vitro release study demonstrated the burst drug release in the beginning and afterwards a sustained release. The cytotoxicity assay exhibited stronger lethal effect towards breast cancer 4T1 cells in company with copper ion. The in vivo study showed the disulfiram loaded biotin-polyethylene glycol 2000- distearyl phosphatidyl ethanolamine modified nanostructured lipid carriers coupled with copper ion were accumulated extensively over time in the tumor through Near Infrared Ray fluorescence imaging study and inhibited tumor growth effectively in the tumor models in breast cancer mice. In our study, biotin-polyethylene glycol 2000- distearyl phosphatidyl ethanolamine modified nanostructured lipid carriers were stable and efficient for disulfiram delivery.

Brittle matrix composites such as concrete are susceptible to damage in the form of cracks. Most of the current self-repair and self-healing techniques have repair limits on crack widths or high costs of an external stimulator, or have an unfavorable effect on the composite’s strength. This paper proposes a new concept of corrosion-induced intelligent fiber (CIF) and a new self-repairing system that uses the CIFs to close cracks in brittle matrix composites within a corrosive environment without external help, and without compromising the strength. The CIF comprises an inner core fiber and an outer corrodible coating that are in equilibrium, with the core fiber in tension and the corrodible coating in compression. The preparation steps and shape recovery mechanism of the CIF and the self-repair mechanism of the CIF composites are explained. Based on these concepts, this paper also describes several mechanical models built to predict the magnitude of pre-stress stored in the core fiber, and the maximum pre-stress released to the matrix composites, and the minimum length of the reliable anchor ends of CIF. The sample calculation results show that the recovery strain was 0.5% for the CIF with the steel core fiber and 12.7% for the CIF with the nylon core fiber; the maximum crack closing force provided by the CIF to concrete can be increased by increasing the amount of the CIFs in concrete and the initial tensile stress of the core fiber. This paper provides some suggestions for enhancing the self-repair capability of brittle composites in complex working environments.

Although chemoimmunotherapy has achieved considerable success in cancer treatment in recent years, the cure for triple-negative breast cancer (TNBC) remains elusive. The unsatisfied outcomes are likely attributed to deficient tumor immunogenicity, a strong immunosuppressive tumor microenvironment (ITM) and tumor metastasis. To address this issue, we constructed an effective codelivery system, combined with tumor growth factor β (TGF-β) small interference RNA (siTGF-β) and shikonin (SK), to achieve successful chemoimmunotherapy of TNBC. The SK/siTGF-β NPs (approximately 110 nm) exhibited a uniform structure and good stability. Conjugated FA presented enhanced cellular uptake in 4T1 cells, and siTGF-β escaped from lysosomes because of the "proton sponge" effect of PEI. Furthermore, SK actually induced satisfactory immunogenic cell death (ICD) and the resulting dendritic cell (DC) maturation facilitated a distinctly enhanced cytotoxic T lymphocyte (CTL) response, generating a positive effect on tumor suppression. Simultaneously, the successful silencing of TGF-β alleviated the TGF-β-mediated ITM and inhibited the epithelial-to-mesenchymal transition (EMT), contributing to the infiltration of CTLs, suppression of regulatory T lymphocyte (Treg) proliferation and lung metastasis inhibition. Thus, the SK/siTGF-β NPs demonstrated the strongest therapeutic effect with delayed tumor growth (TIR = 88.5%) and lung metastasis restraint (77.3%). More importantly, tumor rechallenge assay suggested that the codelivery system produced a long-term immunological memory response to prevent tumor recurrence. Based on boosting the immune response and combating the ITM, SK/siTGF-β NPs would be a potential approach for TNBC therapy.

IR825 is a kind of near-infrared (NIR) small molecule cyanine dye and has distinct near-infrared absorbance and excellent thermal conversion performance. Due to poor stability and insufficient therapy efficacy, various nano-systems have been developed as delivery vehicles for NIR dyes to improve their application in tumor treatment. Herein, we developed an intelligent polymer drug vehicle (Mal-PAH-PEG-DMMA/ poly (ethylene imine) – poly(e-caprolactone) block polymers, MPPD/PEI-PCL) based on pH-responsive charge-reversal to deliver docetaxel (DTX) and photosensitizer (IR825) for chemo-photothermal combination therapy (MPPD@IR825/DTX NPs). MPPD@IR825/DTX NPs could undergo charge conversion in a slightly acidic microenvironment (pH 6.8), resulted in strong electrostatic repulsion to withdraw the shell of the polymer nanoparticles (MPPD), enhanced cellular uptake and increased drug release. MPPD@IR825/DTX NPs demonstrated nanoscale in size with good mono-dispersity and stability, triggered DTX release in response to acid environment and NIR stimulation, in the same time providing excellent photothermal conversion efficiency. In vitro and In vivo experiments confirmed that charge-reversal polymeric nanoparticles improved antitumor efficiency in 4T1 tumor cell modal than non-charge-reversal polymeric nanoparticles. Furthermore, in comparison with chemotherapy or photothermal therapy in a single treatment mode, chemo-photothermal combination therapy of MPPD@IR825/DTX NPs with laser irradiation showed highly efficient tumor ablation. In addition, the polymeric nanoparticles exhibited good biocompatibility and safety. Therefore, the design of charge-reversal polymeric nanoparticles (MPPD@IR825/DTX NPs) provides a new strategy and promising application for targeting and synergistic chemo-photothermal combination therapy.

This paper presents an untethered crawling and jumping micro robot via the frequency of the external alternating magnetic field. The prototype micro robot is 8 mm-long made of soft polymeric materials by a 3D printing process. Two permanent magnets are added to be excited by the low-frequency alternative magnetic field source for the crawling operation. A shape memory alloy (SMA) actuator and an aluminum foil to efficiently stimulate induction heating are utilized under the high-frequency alternative magnetic field for the jumping motion. Under a low driving frequency of 60–90 Hz, the prototype robot can crawl with a speed of 5 body length per second via the induced magnetic force. Under a high driving frequency of 30–40 kHz, induction heating is generated to activate the SMA actuator for the jumping action of up to 30 times of the body height of the robot. By exploring other structural designs and manipulation patterns, various forms of robotic actions and locomotion could be realized to execute complex tasks.

We herein present a soft crawling robot based on the design of the magnetic anisotropic actuation to realize untethered crawling movements. With the self-assembled iron filing mesh tuned magnetically and sealed in silicone rubber matrix, we are able to fabricate a large quantity of crawling robots in parallel by a molding process. The magnetic anisotropy is established in the body of the robot to induce the magnetic actuation. Under an alternating magnetic field near the resonant frequency of the robot, the legs of the robot can bend and release repeatedly to achieve a forward moving velocity of ~0.19 cm/s at 2.5 Hz and 46 mT. In addition, the soft crawling robot is robust enough such that even crushed by a 1.8-ton automobile, it can still be fully functional. We envision the magnetic soft robot design and working principle can be further studied for the advancements of micro-robotics research.

One grand challenge in haptic human-machine interface devices is to electromechanically stimulate sensations on the human skin wirelessly by thin and soft patches under a low driving voltage. Here, we propose a soft haptics-feedback system using highly charged, polymeric electret films with an annulus-shape bump structure to induce mechanical sensations on the fingertip of volunteers under an applied voltage range of 5–20 V. As an application demonstration, a 3 × 3 actuators array is used for transmitting patterned haptic information, such as letters of ‘T’, ‘H’, ‘U’ letters and numbers of ‘0’, ‘1’, ‘2’. Moreover, together with flexible lithium batteries and a flexible circuit board, an untethered stimulation patch is constructed for operations of 1 h. The analytical model, design principle, and performance characterizations can be applicable for the integration of other wearable electronics toward practical applications in the fields of AR (augmented reality), VR (virtual reality) and robotics.

The synergistic therapy of malignant tumors with chemotherapy and photothermal therapy has attracted extensive researcher attention. With the further development of photosensitizers, photosensitizer delivery and stability are the urgent problem to be solved at present. In this study, the biodegradable hybrid micelles (HMs) nano system for co-delivery paclitaxel (PTX) and IR825, investigating the photosensitizer stability in the drug delivery system and therapeutic effectiveness in vitro or in vivo. The hybrid micelle (PTX/IR825-TAT HMs) was self-assembled through hydrophobic interactions between polyethyleneimine-polycaprolactone (PEI-PCL) and TAT peptide modifided-1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-(polyethylene glycol)

One grand challenge in haptic human-machine interface devices is to electromechanically stimulate sensations on human skins wirelessly by thin and soft patches under a low driving voltage. Here, we propose a soft haptics-feedback system using highly charged, polymeric electret films with the annulus-shape bump contact structure to induce mechanical sensations on volunteers under an applied voltage as low as 5 volts. Together with bendable lithium ion batteries and a flexible circuit board, an untethered stimulation patch is constructed for active operations of at least 2 hours with low power consumptions. As an application example, a “silent haptic communication” system is demonstrated to transmit English alphabet letters via the mechanical beating patterns from a patch onto the fingertip of a receiving volunteer. The analytical model, design principle, and performance characterizations can be applicable for the integrations with other devices in wearable electronics toward various applications, including AR (augmented reality) and VR (virtual reality).

Cancer immunotherapy is becoming an important option for malignant tumors treatment. Unfortunately, lacking intratumoral infiltration of cytotoxic T lymphocytes (CTLs) and immunosuppressive tumor microenvironment (ITM) remian primary barriers that immensely hamper its further clinical application. For boosting immune response and rebuilding the ITM, valid hybrid micelles (SK/siIDO1-HMs) delivering shikonin (SK) and IDO-1 knockdown siRNA (siIDO1) were conducted. SK/siIDO1-HMs had sufficient circulation time, favorable intratumoral accumulation and rapidly release in the cytoplasm. Importantly, SK was demonstrated to significantly elicit intratumoral accumulation of CTLs through inducing immunogenic cell death (ICD) of tumor cells. Moreover, siIDO1 downregulated the IDO-1-caused immunosuppression and restrained regulatory T lymphocytes (Tregs). In summary, SK/siIDO1-HMs displayed a remarkable potential for tumor therapy via triggering the ICD and moderating the IDO-1-triggered immunosuppression.

Agility and trajectory control are two desirable features for robotics, but they become very challenging for soft robots without rigid structures to support rapid manipulations. Here, a curved piezoelectric thin film driven at its structural resonant frequency is used as the main body of an insect-scale soft robot for its fast translational movements, and two electrostatic footpads are used for its swift rotational motions. These two schemes are simultaneously executed during operations through a simple two-wire connection arrangement. A high relative centripetal acceleration of 28 body length per square second compared with existing robots is realized on a 65-milligram tethered prototype, which is better than those of common insects, including the cockroach. The trajectory manipulation demonstration is accomplished by navigating the robot to pass through a 120-centimeter-long track in a maze within 5.6 seconds. One potential application is presented by carrying a 180-milligram on-board sensor to record a gas concentration route map and to identify the location of the leakage source. The radically simplified analog motion adjustment technique enables the scale-up construction of a 240-milligram untethered robot. Equipped with a payload of 1660 milligrams to include the control circuit, a battery, and photoresistors, the untethered prototype can follow a designated, 27.9-centimeter-long "S"-shaped path in 36.9 seconds. These results validate key performance attributes in achieving both high mobility and agility to emulate living agile insects for the advancements of soft robots.

The complex physiological barriers impose extremely conflicting demands on systemic drug delivery, so both particle size and surface charge of the nanoplatforms become vital factors. As a carbon-based nanomaterial with excellent optical properties, carbon dots are not suitable for direct systemic transport in vivo, which limits their application in the field of biomedical imaging, especially in the areas of diagnosis and cancer treatment. Liposomes have been developed as universal nanocarriers for various drugs. In this study, we aimed to build a highly precise and penetrative drug delivery system (DDS) using carbon dots encapsulated by liposomes. Carbon dots (CDs) were synthesized by the hydrothermal method using citric acid and ethylenediamine. Furthermore, simian virus 40 large T-antigen derived the nuclear targeting sequence (NLS) was bonded on the surface of CDs to obtain CDs-NLS. The antitumor drug doxorubicin was loaded onto the CDs-NLS through an acid-labile hydrazine bond to obtain DOX@CDs. Finally, DOX@CDs were encapsulated in aqueous centers of folate-coated and pH-sensitive liposomes, named pHSL-FA. In this paper, a nucleus-targeted nanocomposite (DOX@CDs), which bonds with the nuclear targeting sequence (NLS) and the anticancer drug doxorubicin (DOX), has physicochemical properties of particle size of about 3.8 nm, zeta potential of +31.8 mV and high quantum yield of 64.53%. The negatively charged folate-coated and pH-sensitive liposomes (pHSL-FA) are used as a carrier to reverse the surface charge of DOX@CDs. Compared to free DOX@CDs, pHSL-FA show higher tumor accumulation in 4 T1 tumor-bearing mice and further improve cytotoxicity to tumor cells. This work proposes a unique nanomedical approach that enables the precise delivery of chemotherapy drugs and significantly reduces side effects, which is promising for clinical translation.

Monitoring the breath information from two nostrils can detect breath-related health problems. In this work, we introduce a wearable hot-film/calorimetric breath sensing system composed of a hot-film senor in the center and two calorimetric sensors on two sides. This design has the advantages of low power consumption of 60 mW and good sensitivity to simultaneously measure the mix breath velocity and individual breath airflow signals from the two nostrils. In prototype demonstrations, abnormal breath conditions (apnea, hypopnea, polypnea) and the asymmetric breath conditions between the right and left nostril have been recorded and analyzed for potential usages in the diagnosis of specific breath-related diseases.

Nanoparticles (NPs) have proven to be effective drug carriers in diagnosis and therapy of cancer. But, they faced a contradictory issue that NPs with large size appear weak tumor penetration, meanwhile small size resulted in poor tumor retention. Herein, we fabricated doxorubicin conjugated carbon dots (CDs-DOX) and indocyanine green (ICG)-loaded liposomes (ICG-LPs) named CDs-ICG-LPs using a modified reverse phase evaporation process, and with high incorporation in the aqueous core. The CDs-ICG-LPs exhibited good monodispersity, excellent fluorescence/size stability, and consistent spectra characteristics compared with free ICG or DOX. Moreover, the CDs-ICG-LPs showed higher temperature response, faster DOX release under laser irradiation. In the meantime, the fluorescence of DOX and ICG in CDs-ICG-LPs was also visualized for the process of subcellular location in vitro. In comparison with chemo or photothermal treatment alone, the combined treatment of CDs-ICG-LPs with laser irradiation synergistically induced the apoptosis and death of DOX-sensitive HepG2 cells. In vivo antitumor activities demonstrated CDs-ICG-LPs could reach higher antitumor activity compared with CDs-DOX and ICG-LPs for H22 tumor cells, and suppressed H22 tumor growth in vivo. Notably, no systemic toxicity occurrence was observed after repeated dose of CDs-ICG-LPs with laser irradiation. Hence, the well-defined CDs-ICG-LPs exhibited great potential in targeting cancer imaging and chemo-photothermal therapy.