Bioinspired nervous signal transmission system based on two-dimensional laminar nanofluidics: From electronics to ionics.

Mammalian nervous systems, as natural ionic circuitries, stand out in environmental perception and sophisticated information transmission, relying on protein ionic channels and additional necessary structures. Prosperously emerged ionic regulated biomimetic nanochannels exhibit great potentialities in various application scenarios, especially signal transduction. Most reported direct current systems possess deficiencies in informational density and variability, which are superiorities of alternating current (AC) systems and necessities in bioinspired nervous signal transmission. Here, inspired by myelinated saltatory conduction, alternating electrostatic potential controlled nanofluidics are constructed with a noncontact application pattern and MXene nanosheets. Under time-variant external stimuli, ions confined in the interlaminar space obtain the capability of carriers for the AC ionic circuit. The transmitted information is accessible from typical sine to a frequency-modulated binary signal. This work demonstrates the potentiality of the bioinspired nervous signal transmission between electronics and ionic nanofluidics, which might push one step forward to the avenue of AC ionics.

Development of rapamycin-encapsulated exosome-mimetic nanoparticles-in-PLGA microspheres for treatment of hemangiomas.

We have previously developed several kinds of rapamycin-encapsulated nanoparticles to achieve sustained release of rapamycin to treat hemangioma. However, lack of intrinsic targeting and easy clearance by the immune system are major hurdles that artificial fabricated nanoparticles must overcome. We constructed rapamycin-encapsulated macrophage-derived exosomes mimic nanoparticles-in-microspheres (RNM), to achieve the goal of continuous targeted therapy of hemangiomas. The rapamycin-encapsulated exosome mimic nanoparticles (RN) were firstly prepared by the extrusion-based method from the U937 cells (the human macrophage cell line). After then, RN was encapsulated with PLGA (poly(lactic-co-glycolic acid)) microspheres to obtain RNM. The release profile, targeting activity, and biological activity of RN and RNM were investigated on hemangioma stem cells (HemSCs). RN has a size of 100 nm in diameter, with a rapamycin encapsulation efficacy (EE) of 83%. The prepared microspheres RNM have a particle size of ~30 µm), and the drug EE of RNM is 34%. The sustained release of RNM can remarkably be achieved for 40 days. As expected, RN and RNM showed effective inhibition of cellular proliferation, significant cellular apoptosis, and remarkable repressed expression of angiogenesis factors in HemSCs. Our results showed that RNM is an effective approach for prolonged and effective delivery of rapamycin to hemangiomas.

Ultra-Sensitive and Selective Electrochemical Bio-Fluid Biopsy for Oral Cancer Screening.

The early diagnosis of recurrence and metastasis is critically important for decreasing the morbidity and mortality associated with oral cancers. Although liquid biopsy methods hold great promise that provide a successive "time-slice" profile of primary and metastatic oral cancer, the development of non-invasive, rapid, simple, and cost-effective liquid biopsy techniques remains challenging. In this study, an ultrasensitive and selective electrochemical liquid biopsy is developed for oral cancer screening based on tracking trace amounts of cancer biomarker by functionalized asymmetric nano-channels. Detection via antigen-antibody reactions is assayed by evaluating changes in ionic current. Upon the recognition of cancer biomarker antigens in bio-fluids, the inner wall of nano-channel immobilized with the corresponding antibodies undergoes molecular conformation transformation and surface physicochemical changes, which significantly regulate the ion transport through the nano-channel and help achieve sensitivity with a detection limit of 10-12 g mL-1 . Furthermore, owing to the specificity of the monoclonal antibody for the antigen, the nano-channel exhibits high selectivity for the biomarker than for structurally similar biological molecules present in bio-fluids. The effectiveness of this technique is confirmed through the diagnosis of clinical cases of oral squamous cell carcinoma. This study presents a novel diagnostic tool for oral cancer detection in bio-fluids.

Biomimetic Nacre-Like Silk-Crosslinked Membranes for Osmotic Energy Harvesting.

As an approach to harvesting sustainable energy from ambient conditions, the osmotic energy between river water and seawater contributes to solving global issues such as the energy shortage and environmental pollution. Current attempts based on a reverse electrodialysis technique are limited mainly due to the economically unviable power density and inadequate mass transportation of membrane materials. Here, we demonstrate a benign strategy for designing a multilayer graphene oxide-silk nanofiber-graphene oxide biomimetic nacre-like sandwich as an osmotic power generator. Enhanced interfacial bonding endows the composite membranes with long-term stability in saline, and meanwhile, the two-dimensional nanofluidic channel configuration also reduces the ion transport resistance and provides large storage spaces for ions. Thus, the output power density of the proposed membrane-based generator achieves a value of up to 5.07 W m-2 by mixing seawater and river water. Furthermore, we experimentally and theoretically demonstrate that the thermal-field drives the increased output power density due to the advances in ionic movement range and activity of electrode reaction, showing the promise of strengthened thermo-osmotic energy conversion.

Enhanced rapamycin delivery to hemangiomas by lipid polymer nanoparticles coupled with anti-VEGFR antibody.

The most common tumors in children are infantile hemangiomas which could cause morbidity and severe complications. The development of novel alternative drugs to treat infantile hemangiomas is necessary, since Hemangeol is the only US Food and Drug Administration-approved drug for infantile hemangiomas. However, Hemangeol has several disadvantages, including a high frequency of administration and adverse effects. Rapamycin is a well­established antiangiogenic drug, and we have previously developed rapamycin lipid polymer nanoparticles (R­PLNPs) as a local sustained­release drug delivery system to achieve controlled rapamycin release and to decrease the frequency of administration and side effects of rapamycin. To improve the targeting of R­PLNPs to infantile hemangiomas in the present study, R­PLNPs were modified to include an antibody against vascular endothelial growth factor receptor (VEGF). The characteristics, and the anti­hemangioma activity of the resulting R­PLNPs coupled with the anti­VEGFR2 antibody (named R­PLNPs­V) were examined in vitro and in vivo. R­PLNPs­V possessed a small size (115 nm) and sustained drug release for 6 days. The anti­VEGFR2 antibody promoted the targeting and cytotoxic effect of R­PLNPs­V to human hemangioma endothelial cells and human umbilical vein endothelial cells. Using a subcutaneous infantile hemangioma xenograft in mice, the in vivo therapeutic effect (evaluated with hemangioma weight, volume, and microvessel density) of R­PLNPs­V was demonstrated to be superior compared with rapamycin alone and other non­targeted nanoparticles, without any total body weight loss. In summary, R­PLNPs­V could facilitate targeted delivery and sustained release of rapamycin to infantile hemangiomas, and thus may represent a promising candidate treatment for infantile hemangiomas.

Inhibition of hemangioma growth using polymer-lipid hybrid nanoparticles for delivery of rapamycin.

Although infantile hemangiomas is benign, its rapid growth may induce serious complications. However, only one drug Hemangeol™ has been approved by US Food and Drug Administration (FDA) to treat infantile hemangiomas. Thus it is necessary to develop novel alternative drugs to treat infantile hemangiomas. Rapamycin is a well-know potent antiangiogenic agent, whereas the daily oral administration of rapamycin exerts undesired metabolic effects due to its inhibition of mechanistic target of rapamycin (mTOR) which is critical in cell metabolism. We hereby developed rapamycin-loaded polymer-lipid hybrid nanoparticles (Rapamycin-PLNPs) as a local controlled release system to realize local and sustained release of rapamycin, aiming to reduce the side effects and frequency of administration of rapamycin. Rapamycin-PLNPs are of a small size (129.1nm), desired drug encapsulation efficiency (63.7%), and sustained drug release for 5 days. Rapamycin-PLNPs were shown to be able to effectively bind to hemangioma endothelia cells (HemECs), induce significant proliferation inhibition and reduce expression of angiogenesis factors in HemECs. The therapeutic effect of Rapamycin-PLNPs against infantile hemangioma in vivo was superior to rapamycin, as reflected by reduced hemangioma volume, weight and microvessel density. Taken together, Rapamycin-PLNPs represent a very promising local approach in the treatment of infantile hemangiomas.