Rational Design of a Flexible CNTs@PDMS Film Patterned by Bio‐Inspired Templates as a Strain Sensor and Supercapacitor

Flexible devices integrated with sensing and energy storage functions are highly desirable due to their potential application in wearable electronics and human motion detection. Here, a flexible film is designed in a facile and low‐cost leaf templating process, comprising wrinkled carbon nanotubes (CNTs) as the conductive layer and patterned polydimethylsiloxane (PDMS) with bio‐inspired microstructure as a soft substrate. Assembled from wrinkled CNTs on patterned PDMS film, a strain sensor is realized to possess sensitive resistance response against various deformations, producing a resistance response of 0.34%, 0.14%, and 9.1% under bending, pressing, and 20% strain, respectively. Besides, the strain sensor can reach a resistance response of 3.01 when stretched to 44%. Furthermore, through the electro‐deposition of polyaniline, the CNTs film is developed into a supercapacitor, which exhibits a specific capacitance of 176 F g^?1 at 1 A g^?1 and a capacitance retention of 88% after 10 000 cycles. In addition, the fabricated supercapacitor shows super flexibility, delivering a capacitance retention of 98% after 180° bending for 100 cycles, 95% after 45° twisting for 100 cycles, and 98% after 100% stretching for 400 cycles. The superior capacitance stability demonstrates that the design of wrinkled CNTs‐based electrodes fixed by microstructures is beneficial to the excellent electrochemical performance.     

Red Blood Cell Membrane as a Biomimetic Nanocoating for Prolonged Circulation Time and Reduced Accelerated Blood Clearance

For decades, poly(ethylene glycol) (PEG) has been widely incorporated into nanoparticles for evading immune clearance and improving the systematic circulation time. However, recent studies have reported a phenomenon known as “accelerated blood clearance (ABC)” where a second dose of PEGylated nanomaterials is rapidly cleared when given several days after the first dose. Herein, we demonstrate that natural red blood cell (RBC) membrane is a superior alternative to PEG. Biomimetic RBC membrane‐coated Fe₃O₄ nanoparticles (Fe₃O₄@RBC NPs) rely on CD47, which is a “don't eat me” marker on the RBC surface, to escape immune clearance through interactions with the signal regulatory protein‐alpha (SIRP‐α) receptor. Fe₃O₄@RBC NPs exhibit extended circulation time and show little change between the first and second doses, with no ABC suffered. In addition, the administration of Fe₃O₄@RBC NPs does not elicit immune responses on neither the cellular level (myeloid‐derived suppressor cells (MDSCs)) nor the humoral level (immunoglobulin M and G (IgM and IgG)). Finally, the in vivo toxicity of these cell membrane‐camouflaged nanoparticles is systematically investigated by blood biochemistry, hematology testing, and histology analysis. These findings are significant advancements toward solving the long‐existing clinical challenges of developing biomaterials that are able to resist both immune response and rapid clearance.     

Erythrocyte‐Membrane‐Enveloped Perfluorocarbon as Nanoscale Artificial Red Blood Cells to Relieve Tumor Hypoxia and Enhance Cancer Radiotherapy

Hypoxia, a common feature within many types of solid tumors, is known to be closely associated with limited efficacy for cancer therapies, including radiotherapy (RT) in which oxygen is essential to promote radiation‐induced cell damage. Here, an artificial nanoscale red‐blood‐cell system is designed by encapsulating perfluorocarbon (PFC), a commonly used artificial blood substitute, within biocompatible poly(d ,l ‐lactide‐co‐glycolide) (PLGA), obtaining PFC@PLGA nanoparticles, which are further coated with a red‐blood‐cell membrane (RBCM). The developed PFC@PLGA‐RBCM nanoparticles with the PFC core show rather efficient loading of oxygen, as well as greatly prolonged blood circulation time owing to the coating of RBCM. With significantly improved extravascular diffusion within the tumor mass, owing to their much smaller nanoscale sizes compared to native RBCs with micrometer sizes, PFC@PLGA‐RBCM nanoparticles are able to effectively deliver oxygen into tumors after intravenous injection, leading to greatly relieved tumor hypoxia and thus remarkably enhanced treatment efficacy during RT. This work thus presents a unique type of nanoscale RBC mimic for efficient oxygen delivery into solid tumors, favorable for cancer treatment by RT, and potentially other types of therapy as well.     

Bio‐Orthogonal T Cell Targeting Strategy for Robustly Enhancing Cytotoxicity against Tumor Cells

T cells can kill tumor cells by cell surface immunological recognition, but low affinity for tumor‐associated antigens could lead to T cell off‐target effects. Herein, a universal T cell targeting strategy based on bio‐orthogonal chemistry and glycol‐metabolic engineering is introduced to enhance recognition and cytotoxicity of T cells in tumor immunotherapy. Three kinds of bicycle [6.1.0] nonyne (BCN)‐modified sugars are designed and synthesized, in which Ac₄ManN‐BCN shows efficient incorporation into wide tumor cells with a BCN motif on surface glycans. Meanwhile, activated T cells are treated with Ac₄GalNAz to introduce azide (N₃) on the cell surface, initiating specific tumor targeting through a bio‐orthogonal click reaction between N₃ and BCN. This artificial targeting strategy remarkably enhances recognition and migration of T cells to tumor cells, and increases the cytotoxicity 2 to 4 times for T cells against different kinds of tumor cells. Surprisingly, based on this strategy, the T cells even exhibit similar cytotoxicity with the chimeric antigen receptor T‐cell against Raji cells in vitro at the effector: target cell ratios (E:T) of 1:1. Such a universal bio‐orthogonal T cell‐targeting strategy might further broaden applications of T cell therapy against tumors and provide a new strategy for T cell modification.     

Virus‐Inspired Nanogenes Free from Man‐Made Materials for Host‐Specific Transfection and Bio‐Aided MR Imaging

Many viruses have a lipid envelope derived from the host cell membrane that contributes much to the host specificity and the cellular invasion. This study puts forward a virus‐inspired technology that allows targeted genetic delivery free from man‐made materials. Genetic therapeutics, metal ions, and biologically derived cell membranes are nanointegrated. Vulnerable genetic therapeutics contained in the formed “nanogene” can be well protected from unwanted attacks by blood components and enzymes. The surface envelope composed of cancer cell membrane fragments enables host‐specific targeting of the nanogene to the source cancer cells and homologous tumors while effectively inhibiting recognition by macrophages. High transfection efficiency highlights the potential of this technology for practical applications. Another unique merit of this technology arises from the facile combination of special biofunction of metal ions with genetic therapy. Typically, Gd(III)‐involved nanogene generates a much higher T₁ relaxation rate than the clinically used Gd magnetic resonance imaging agent and harvests the enhanced MRI contrast at tumors. This virus‐inspired technology points out a distinctive new avenue for the disease‐specific transport of genetic therapeutics and other biomacromolecules.     

High Aspect Ratio Sub‐Micrometer Channels Using Wet Etching: Application to the Dynamics of Red Blood Cell Transiting through Biomimetic Splenic Slits

Nanoparticles delivering drugs, disseminating cancer cells, and red blood cells (RBCs) during splenic filtration must deform and pass through the sub‐micrometer and high aspect ratio interstices between the endothelial cells lining blood vessels. The dynamics of passage of particles/cells through these slit‐like interstices remain poorly understood because the in vitro reproduction of slits with physiological dimensions in devices compatible with optical microscopy observations requires expensive technologies. Here, novel microfluidic PDMS devices containing high aspect ratio slits with sub‐micrometer width are molded on silicon masters using a simple, inexpensive, and highly flexible method combining standard UV lithography and anisotropic wet etching. These devices enabled revealing novel modes of deformations of healthy and diseased RBCs squeezing through splenic‐like slits (0.6–2 × 5–10 × 1.6–11 µm³) under physiological interstitial pressures. At the slit exit, the cytoskeleton of spherocytic RBCs seemed to be detached from the lipid membrane whereas RBCs from healthy donors and patients with sickle cell disease exhibited peculiar tips at their front. These tips disappeared much slower in patients' cells, allowing estimating a threefold increase in RBC cytoplasmic viscosity in sickle cell disease. Measurements of time and rate of RBC sequestration in the slits allowed quantifying the massive trapping of spherocytic RBCs.     

Fabrication and Characteristics of Microbial Time Temperature Indicators from Bio‐Paste Using Screen Printing Method

Screen printing method was employed to produce microbial time temperature indicators (TTI). Bio‐pastes containing lactic acid bacteria loaded Ca‐alginate microparticles (LCAMs) and suitable for printing on polymer films have been produced. Through a spray‐solidification method, polysaccharide gel microparticles allowed for the efficient encapsulation of the lactic acid bacteria, which chromatically induced a colour change in the pH indicator. As the alginate concentration of LCAMs increased, the size of the microparticles decreased. The average diameter of LCAMs ranged from (1.67 ± 0.15) × 10³ to (2.93 ± 0.31) × 10³ nm. For the evaluation of bio‐pastes, the contact angles and lactic acid production properties were determined. Lower contact angles were obtained with decreasing pullulan concentration, indicating the increase in wettability for printing. The curve of lactic acid production by alginate immobilized cells was determined to take place as a zero‐order reaction favourable to TTI colour change. Visibility of TTIs was greatly improved at microencapsulation sites. As the size of the LCAMs was decreased, the visibility was found to be improved. The Arrhenius activation energy (Ea) of CIFP009‐based TTI was 117 kJ/mol. The results show that the developed manufacturing method would be used for an industrialized, simple and low‐cost manufacturing method for microbial TTIs. Copyright © 2013 John Wiley & Sons, Ltd.     

Surface‐Engineering of Red Blood Cells as Artificial Antigen Presenting Cells Promising for Cancer Immunotherapy

The development of artificial antigen presenting cells (aAPCs) to mimic the functions of APCs such as dendritic cells (DCs) to stimulate T cells and induce antitumor immune responses has attracted substantial interests in cancer immunotherapy. In this work, a unique red blood cell (RBC)‐based aAPC system is designed by engineering antigen peptide‐loaded major histocompatibility complex‐I and CD28 activation antibody on RBC surface, which are further tethered with interleukin‐2 (IL2) as a proliferation and differentiation signal. Such RBC‐based aAPC‐IL2 (R‐aAPC‐IL2) can not only provide a flexible cell surface with appropriate biophysical parameters, but also mimic the cytokine paracrine delivery. Similar to the functions of matured DCs, the R‐aAPC‐IL2 cells can facilitate the proliferation of antigen‐specific CD8+ T cells and increase the secretion of inflammatory cytokines. As a proof‐of‐concept, we treated splenocytes from C57 mice with R‐aAPC‐IL2 and discovered those splenocytes induced significant cancer‐cell‐specific lysis, implying that the R‐aAPC‐IL2 were able to re‐educate T cells and induce adoptive immune response. This work thus presents a novel RBC‐based aAPC system which can mimic the functions of antigen presenting DCs to activate T cells, promising for applications in adoptive T cell transfer or even in direct activation of circulating T cells for cancer immunotherapy.     

Development of Blood‐Cell‐Selective Fluorescent Biodots for Lysis‐Free Leukocyte Imaging and Differential Counting in Whole Blood

Complete blood count with leukocyte (white blood cell, WBC) differential is one of the most frequently ordered clinical test for disease diagnosis. Herein, multifunctional fluorescent carbon dots derived from biomolecules (biodots) for rapid lysis‐free whole blood analysis are developed. Specifically, two types of biodots are molecularly engineered through hydrothermal synthesis for differential blood cells labeling. Type I biodots synthesized from amino acid (serine/threonine) precursors and passivated with polyethylenimine can label both red blood cells (RBCs) and WBCs with excellent contrast in fluorescence intensity, enabling direct counting of leukocytes in whole blood samples without a tedious RBC lysis step. It also allows three‐part leukocyte differential counting by flow cytometry without using expensive fluorophore‐conjugated antibodies. On the other hand, Type II biodots synthesized from the same amino acid precursors but passivated with a biopolymer (chitosan) are able to selectively lyse RBCs with greater than 98% efficiency to allow simultaneous fluorescent labeling of leukocytes for WBC counting in whole blood. It is envisioned that these novel nanoreagents, which eliminate the cumbersome lysis and antibody conjugation steps for selective labeling of different blood cells, would revolutionize disease diagnostics toward achieving faster, cheaper, and more accurate whole blood analyses in one test.