bims-drudre Biomed News
on Targeted drug delivery and programmed release mechanisms
Issue of 2021–03–21
seventeen papers selected by
Ceren Kimna, Technical University of Munich
  1. Cancer cells escape autophagy inhibition via NRF2-induced macropinocytosis.
  2. Single-component, self-assembling, protein nanoparticles presenting the receptor binding domain and stabilized spike as SARS-CoV-2 vaccine candidates.
  3. Self-Activated Cascade-Responsive Sorafenib and USP22 shRNA Co-Delivery System for Synergetic Hepatocellular Carcinoma Therapy.
  4. Targeting immunosuppressive macrophages overcomes PARP inhibitor resistance in BRCA1-associated triple-negative breast cancer.
  5. Immunoediting role for major vault protein in apoptotic signaling induced by bacterial N-acyl homoserine lactones.
  6. Sequential Release of Pooled siRNAs and Paclitaxel by Aptamer-Functionalized Shell-Core Nanoparticles to Overcome Paclitaxel Resistance of Prostate Cancer.
  7. Functionalization of Cellular Membranes with DNA Nanotechnology.
  8. Assessment of medication self-administration using artificial intelligence.
  9. Modularly Programmable Nanoparticle Vaccine Based on Polyethyleneimine for Personalized Cancer Immunotherapy.
  10. Profiling MicroRNAs with Associated Spatial Dynamics in Acute Tissue Slices.
  11. Targeting miR-148b-5p Inhibits Immunity Microenvironment and Gastric Cancer Progression.
  12. CRISPR-Guided Programmable Self-Assembly of Artificial Virus-Like Nucleocapsids.
  13. Biological Mediator-Propelled Nanosweeper for Nonpharmaceutical Thrombus Therapy.
  14. Janus Nanosheets with Face-Selective Molecular Recognition Properties from DNA-Peptide Conjugates.
  15. miR-153 enhances the therapeutic effect of radiotherapy by targeting JAG1 in pancreatic cancer cells.
  16. Nano-ghosts: Novel biomimetic nano-vesicles for the delivery of antisense oligonucleotides.
  17. Programmable Design and Performance of Modular Magnetic Microswimmers.
  1. Cancer Cell. 2021 Mar 10. pii: S1535-6108(21)00118-5. [Epub ahead of print]
    Cancer cells escape autophagy inhibition via NRF2-induced macropinocytosis.
    Hua Su, Fei Yang, Rao Fu, Xin Li, Randall French, Evangeline Mose, Xiaohong Pu, Brittney Trinh, Avi Kumar, Junlai Liu, Laura Antonucci, Jelena Todoric, Yuan Liu, Yinling Hu, Maria T Diaz-Meco, Jorge Moscat, Christian M Metallo, Andrew M Lowy, Beicheng Sun, Michael Karin.
      Many cancers, including pancreatic ductal adenocarcinoma (PDAC), depend on autophagy-mediated scavenging and recycling of intracellular macromolecules, suggesting that autophagy blockade should cause tumor starvation and regression. However, until now autophagy-inhibiting monotherapies have not demonstrated potent anti-cancer activity. We now show that autophagy blockade prompts established PDAC to upregulate and utilize an alternative nutrient procurement pathway: macropinocytosis (MP) that allows tumor cells to extract nutrients from extracellular sources and use them for energy generation. The autophagy to MP switch, which may be evolutionarily conserved and not cancer cell restricted, depends on activation of transcription factor NRF2 by the autophagy adaptor p62/SQSTM1. NRF2 activation by oncogenic mutations, hypoxia, and oxidative stress also results in MP upregulation. Inhibition of MP in autophagy-compromised PDAC elicits dramatic metabolic decline and regression of transplanted and autochthonous tumors, suggesting the therapeutic promise of combining autophagy and MP inhibitors in the clinic.
    Keywords:  NRF2; RAS-driven cancer; autophagy; macropinocytosis; p62/SQSTM1
    DOI:  https://doi.org/10.1016/j.ccell.2021.02.016
  2. Sci Adv. 2021 Mar;pii: eabf1591. [Epub ahead of print]7(12):
    Single-component, self-assembling, protein nanoparticles presenting the receptor binding domain and stabilized spike as SARS-CoV-2 vaccine candidates.
    Linling He, Xiaohe Lin, Ying Wang, Ciril Abraham, Cindy Sou, Timothy Ngo, Yi Zhang, Ian A Wilson, Jiang Zhu.
      Vaccination against SARS-CoV-2 provides an effective tool to combat the COVID-19 pandemic. Here, we combined antigen optimization and nanoparticle display to develop vaccine candidates for SARS-CoV-2. We first displayed the receptor-binding domain (RBD) on three self-assembling protein nanoparticle (SApNP) platforms using the SpyTag/SpyCatcher system. We then identified heptad repeat 2 (HR2) in S2 as the cause of spike metastability, designed an HR2-deleted glycine-capped spike (S2GΔHR2), and displayed S2GΔHR2 on SApNPs. An antibody column specific for the RBD enabled tag-free vaccine purification. In mice, the 24-meric RBD-ferritin SApNP elicited a more potent neutralizing antibody (NAb) response than the RBD alone and the spike with two stabilizing proline mutations in S2 (S2P). S2GΔHR2 elicited twofold higher NAb titers than S2P, while S2GΔHR2 SApNPs derived from multilayered E2p and I3-01v9 60-mers elicited up to 10-fold higher NAb titers. The S2GΔHR2-presenting I3-01v9 SApNP also induced critically needed T cell immunity, thereby providing a promising vaccine candidate.
    DOI:  https://doi.org/10.1126/sciadv.abf1591
  3. Adv Sci (Weinh). 2021 Mar;8(5): 2003042
    Self-Activated Cascade-Responsive Sorafenib and USP22 shRNA Co-Delivery System for Synergetic Hepatocellular Carcinoma Therapy.
    Shengjun Xu, Sunbin Ling, Qiaonan Shan, Qianwei Ye, Qifan Zhan, Guangjiang Jiang, Jianyong Zhuo, Binhua Pan, Xue Wen, Tingting Feng, Haohao Lu, Xuyong Wei, Haiyang Xie, Shusen Zheng, Jiajia Xiang, Youqing Shen, Xiao Xu.
      Resistance to sorafenib severely hinders its effectiveness against hepatocellular carcinoma (HCC). Cancer stemness is closely connected with resistance to sorafenib. Methods for reversing the cancer stemness remains one of the largest concerns in research and the lack of such methods obstructs current HCC therapeutics. Ubiquitin-specific protease 22 (USP22) is reported to play a pivotal role in HCC stemness and multidrug resistance (MDR). Herein, a galactose-decorated lipopolyplex (Gal-SLP) is developed as an HCC-targeting self-activated cascade-responsive nanoplatform to co-delivery sorafenib and USP22 shRNA (shUSP22) for synergetic HCC therapy. Sorafenib, entrapped in the Gal-SLPs, induced a reactive oxygen species (ROS) cascade and triggered rapid shUSP22 release. Thus, Gal-SLPs dramatically suppressed the expression of USP22. The downregulation of USP22 suppresses multidrug resistance-associated protein 1 (MRP1) to induce intracellular sorafenib accumulation and hampers glycolysis of HCC cells. As a result, Gal-SLPs efficiently inhibit the viability, proliferation, and colony formation of HCC cells. A sorafenib-insensitive patient-derived xenograft (PDX) model is established and adopted to evaluate in vivo antitumor effect of Gal-SLPs. Gal-SLPs exhibit potent antitumor efficiency and biosafety. Therefore, Gal-SLPs are expected to have great potential in the clinical treatment of HCC.
    Keywords:  USP22 shRNA; cascade‐responsive; co‐delivery; hepatocellular carcinoma; sorafenib
    DOI:  https://doi.org/10.1002/advs.202003042
  4. Nat Cancer. 2021 Jan;2(1): 66-82
    Targeting immunosuppressive macrophages overcomes PARP inhibitor resistance in BRCA1-associated triple-negative breast cancer.
    Anita K Mehta, Emily M Cheney, Christina A Hartl, Constantia Pantelidou, Madisson Oliwa, Jessica A Castrillon, Jia-Ren Lin, Katie E Hurst, Mateus de Oliveira Taveira, Nathan T Johnson, William M Oldham, Marian Kalocsay, Matthew J Berberich, Sarah A Boswell, Aditi Kothari, Shawn Johnson, Deborah A Dillon, Mikel Lipschitz, Scott Rodig, Sandro Santagata, Judy E Garber, Nadine Tung, José Yélamos, Jessica E Thaxton, Elizabeth A Mittendorf, Peter K Sorger, Geoffrey I Shapiro, Jennifer L Guerriero.
      Despite objective responses to PARP inhibition and improvements in progression-free survival compared to standard chemotherapy in patients with BRCA-associated triple-negative breast cancer (TNBC), benefits are transitory. Using high dimensional single-cell profiling of human TNBC, here we demonstrate that macrophages are the predominant infiltrating immune cell type in BRCA-associated TNBC. Through multi-omics profiling we show that PARP inhibitors enhance both anti- and pro-tumor features of macrophages through glucose and lipid metabolic reprogramming driven by the sterol regulatory element-binding protein 1 (SREBP-1) pathway. Combined PARP inhibitor therapy with CSF-1R blocking antibodies significantly enhanced innate and adaptive anti-tumor immunity and extends survival in BRCA-deficient tumors in vivo and is mediated by CD8+ T-cells. Collectively, our results uncover macrophage-mediated immune suppression as a liability of PARP inhibitor treatment and demonstrate combined PARP inhibition and macrophage targeting therapy induces a durable reprogramming of the tumor microenvironment, thus constituting a promising therapeutic strategy for TNBC.
    DOI:  https://doi.org/10.1038/s43018-020-00148-7
  5. Proc Natl Acad Sci U S A. 2021 Mar 23. pii: e2012529118. [Epub ahead of print]118(12):
    Immunoediting role for major vault protein in apoptotic signaling induced by bacterial N-acyl homoserine lactones.
    Josep Rayo, Rachel Gregor, Nicholas T Jacob, Rambabu Dandela, Luba Dubinsky, Alex Yashkin, Alexander Aranovich, Manikandan Thangaraj, Orna Ernst, Eran Barash, Sergey Malitsky, Bogdan I Florea, Bastiaan P Krom, Erik A C Wiemer, Valerie A Kickhoefer, Leonard H Rome, John C Mathison, Gunnar F Kaufmann, Herman S Overkleeft, Benjamin F Cravatt, Tsaffrir Zor, Kim D Janda, Richard J Ulevitch, Vladimir V Kravchenko, Michael M Meijler.
      The major vault protein (MVP) mediates diverse cellular responses, including cancer cell resistance to chemotherapy and protection against inflammatory responses to Pseudomonas aeruginosa Here, we report the use of photoactive probes to identify MVP as a target of the N-(3-oxo-dodecanoyl) homoserine lactone (C12), a quorum sensing signal of certain proteobacteria including P. aeruginosa. A treatment of normal and cancer cells with C12 or other N-acyl homoserine lactones (AHLs) results in rapid translocation of MVP into lipid raft (LR) membrane fractions. Like AHLs, inflammatory stimuli also induce LR-localization of MVP, but the C12 stimulation reprograms (functionalizes) bioactivity of the plasma membrane by recruiting death receptors, their apoptotic adaptors, and caspase-8 into LR. These functionalized membranes control AHL-induced signaling processes, in that MVP adjusts the protein kinase p38 pathway to attenuate programmed cell death. Since MVP is the structural core of large particles termed vaults, our findings suggest a mechanism in which MVP vaults act as sentinels that fine-tune inflammation-activated processes such as apoptotic signaling mediated by immunosurveillance cytokines including tumor necrosis factor-related apoptosis inducing ligand (TRAIL).
    Keywords:  bacterial signaling; cross-kingdom communication; immunoediting; immunosurveillance
    DOI:  https://doi.org/10.1073/pnas.2012529118
  6. ACS Appl Mater Interfaces. 2021 Mar 19.
    Sequential Release of Pooled siRNAs and Paclitaxel by Aptamer-Functionalized Shell-Core Nanoparticles to Overcome Paclitaxel Resistance of Prostate Cancer.
    Qianqian Guo, Yang Dong, Yanhua Zhang, Hao Fu, Chuanrong Chen, Liting Wang, Xupeng Yang, Ming Shen, Jian Yu, Meiwan Chen, Jiali Zhang, Yourong Duan.
      Paclitaxel (PTX) is a first-line chemotherapeutic agent to treat prostate cancer (PCa), but a large number of patients acquired drug resistance after short-term treatment. To develop combinational therapeutics to overcome PTX-resistant PCa, we established PTX-resistant LNCaP (LNCaP/PTX) cells and found that the LNCaP/PTX cells exhibited epithelial-mesenchymal transition (EMT) and enhanced metastasis during the selection process. We revealed that β-tubulin III, androgen receptor, and CXCR4 expressions were significantly increased in LNCaP/PTX cells and directly contributed to PTX resistance and EMT. Therefore, we developed prostate-specific membrane antigen aptamer (Apt)-functionalized shell-core nanoparticles (PTX/siRNAs NPs-Apt); the hydrophobic DSPE encapsulating PTX formed the dense inner core and the hydrophilic Apt-PEG2K with calcium phosphate (CaP) absorbing siRNAs formed the outer shell to sequentially release siRNAs and PTX, where CaP could trigger lysosomal escape to ensure that pooled siRNAs efficiently released into the cytoplasm to reverse EMT and resensitize PTX, while the PTX located in the core was subsequently released to exert the killing effect of chemotherapy to achieve the best synergistic effect. PTX/siRNAs NPs-Apt showed an enhanced tumor-targeting ability and achieved superior efficacy in the subcutaneous and orthotopic PCa tumor model with minimal side effects.
    Keywords:  PTX-resistant prostate cancer; aptamer; combinational therapy; epithelial−mesenchymal transition; sequential release
    DOI:  https://doi.org/10.1021/acsami.1c00852
  7. Trends Biotechnol. 2021 Mar 12. pii: S0167-7799(21)00034-2. [Epub ahead of print]
    Functionalization of Cellular Membranes with DNA Nanotechnology.
    Andreas Schoenit, Elisabetta Ada Cavalcanti-Adam, Kerstin Göpfrich.
      Due to its versatility and programmability, DNA nanotechnology has greatly expanded the experimental toolbox for biomedical research. Recent advances allow reliable and efficient functionalization of cellular plasma membranes with a variety of synthetic DNA constructs, ranging from single strands to complex 3D DNA origami. The scope for applications, which probe biophysical parameters or equip cells with novel functions, is rapidly increasing. These applications extend from programmed cellular connectivity and tissue engineering to molecular force measurements, controlled receptor-ligand interactions, membrane-anchored biosensors, and artificial transmembrane structures. Here, we give guidance on different strategies to functionalize cellular membranes with DNA nanotechnology and summarize current trends employing membrane-anchored DNA as a tool in biophysics, cell biology, and synthetic biology.
    Keywords:  DNA nanotechnology; DNA origami; cell biology; cellular plasma membrane; lipid bilayer; membrane engineering
    DOI:  https://doi.org/10.1016/j.tibtech.2021.02.002
  8. Nat Med. 2021 Mar 18.
    Assessment of medication self-administration using artificial intelligence.
    Mingmin Zhao, Kreshnik Hoti, Hao Wang, Aniruddh Raghu, Dina Katabi.
      Errors in medication self-administration (MSA) lead to poor treatment adherence, increased hospitalizations and higher healthcare costs. These errors are particularly common when medication delivery involves devices such as inhalers or insulin pens. We present a contactless and unobtrusive artificial intelligence (AI) framework that can detect and monitor MSA errors by analyzing the wireless signals in the patient's home, without the need for physical contact. The system was developed by observing self-administration conducted by volunteers and evaluated by comparing its prediction with human annotations. Findings from this study demonstrate that our approach can automatically detect when patients use their inhalers (area under the curve (AUC) = 0.992) or insulin pens (AUC = 0.967), and assess whether patients follow the appropriate steps for using these devices (AUC = 0.952). The work shows the potential of leveraging AI-based solutions to improve medication safety with minimal overhead for patients and health professionals.
    DOI:  https://doi.org/10.1038/s41591-021-01273-1
  9. Adv Sci (Weinh). 2021 Mar;8(5): 2002577
    Modularly Programmable Nanoparticle Vaccine Based on Polyethyleneimine for Personalized Cancer Immunotherapy.
    Jutaek Nam, Sejin Son, Kyung Soo Park, James J Moon.
      Nanoparticles (NPs) can serve as a promising vaccine delivery platform for improving pharmacological property and codelivery of antigens and adjuvants. However, NP-based vaccines are generally associated with complex synthesis and postmodification procedures, which pose technical and manufacturing challenges for tailor-made vaccine production. Here, modularly programmed, polyethyleneimine (PEI)-based NP vaccines are reported for simple production of personalized cancer vaccines. Briefly, PEI is conjugated with neoantigens by facile coupling chemistry, followed by electrostatic assembly with CpG adjuvants, leading to the self-assembly of nontoxic, sub-50 nm PEI NPs. Importantly, PEI NPs promote activation and antigen cross-presentation of antigen-presenting cells and cross-priming of neoantigen-specific CD8+ T cells. Surprisingly, after only a single intratumoral injection, PEI NPs with optimal PEGylation elicit as high as ≈30% neoantigen-specific CD8+ T cell response in the systemic circulation and sustain elevated CD8+ T cell response over 3 weeks. PEI-based nanovaccines exert potent antitumor efficacy against pre-established local tumors as well as highly aggressive metastatic tumors. PEI engineering for modular incorporation of neoantigens and adjuvants offers a promising strategy for rapid and facile production of personalized cancer vaccines.
    Keywords:  cancer vaccines; immunotherapy; nanoparticles; neoantigens
    DOI:  https://doi.org/10.1002/advs.202002577
  10. ACS Nano. 2021 Mar 10.
    Profiling MicroRNAs with Associated Spatial Dynamics in Acute Tissue Slices.
    Kai Xie, Zixun Wang, Lin Qi, Xi Zhao, Yuan Wang, Jin Qu, Ping Xu, Linfeng Huang, Wenjun Zhang, Yang Yang, Xin Wang, Peng Shi.
      MicroRNAs (miRNAs) are suggested to play important roles in the pathogenesis and progress of human diseases with heterogeneous regulation in different types of cells. However, limited technique is available for profiling miRNAs with both expression and spatial dynamics. Here, we describe a platform for multiplexed in situ miRNA profiling in acute tissue slices. The technique uses diamond nanoneedles functionalized with RNA-binding proteins to directly isolate targeted miRNAs from the cytosol of a large population of cells to achieve a quasi-single-cell analysis for a tissue sample. In addition to a quantitative evaluation of the expression level of particular miRNAs, the technique also provides the relative spatial dynamics of the cellular miRNAs in associated cell populations, which was demonstrated to be useful in analyzing the susceptibility and spatial reorganization of different types of cells in the tissues from normal or diseased animals. As a proof-of-concept, in MK-801-induced schizophrenia model, we found that astrocytes, instead of neurons, are more heterogeneously affected in the hippocampus of rats that underwent repeated injection of MK-801, showing an expression fingerprint related to differentially down-regulated miRNA-135a and miRNA-143; the associated astrocyte subpopulation is also more spatially dispersed in the hippocampus, suggesting an astrocyte dysregulation in the induced schizophrenia animals.
    Keywords:  brain disease; cellular heterogeneity; diamond nanoneedles; in situ profiling; microRNA; spatial transcriptome
    DOI:  https://doi.org/10.1021/acsnano.0c09676
  11. Front Immunol. 2021 ;12 590447
    Targeting miR-148b-5p Inhibits Immunity Microenvironment and Gastric Cancer Progression.
    Yuyu Zhang, Wei Huo, Lidi Sun, Jie Wu, Chengbin Zhang, Huanhuan Wang, Bin Wang, Jinlong Wei, Chao Qu, Hongshi Cao, Xin Jiang.
       Background: MicroRNAs (miRNAs) have been discovered to dictate the development of various tumors. However, studies on the roles of miRNAs in the progression of gastric cancer (GC) are still lacking.
    Methods: Herein, by analyzing GC cell lines and patients samples, we observed that miR-148b-5p was significantly downregulated in GC. We also confirmed that miR-148b-5p overexpression significantly inhibited GC cell proliferation and invasion in vitro and in vivo.
    Results: Overexpression of miR-148b-5p not only reprogrammed the metabolic properties of GC but also regulated the immune microenvironment by shifting lymphocyte and myeloid populations. Mechanistically, ATPIF1, an important glycolysis-associated gene, was identified as a direct target of miR-148b-5p and mediated the effect of miR-148b-5p. Notably, the low level of miR-148b-5p was significantly related with poor prognosis of GC patients (P < 0.001). Importantly, the levels of miR-148b-5p significantly changed the sensitivity of GC cells to several anti-cancer drugs (Doxorubicin, P < 0.05, Paclitaxel, P < 0.01, Docetaxel, P < 0.05).
    Conclusions: Targeting miR-148b-5p inhibits immunity microenvironment and gastric cancer progression.
    Keywords:  ATPIF1; gastric cancer; immune microenvironment; metabolic reprogramming; miR-148b-5p
    DOI:  https://doi.org/10.3389/fimmu.2021.590447
  12. Nano Lett. 2021 Mar 17.
    CRISPR-Guided Programmable Self-Assembly of Artificial Virus-Like Nucleocapsids.
    Carlos Calcines-Cruz, Ilya J Finkelstein, Armando Hernandez-Garcia.
      Designer virus-inspired proteins drive the manufacturing of more effective, safer gene-delivery systems and simpler models to study viral assembly. However, self-assembly of engineered viromimetic proteins on specific nucleic acid templates, a distinctive viral property, has proved difficult. Inspired by viral packaging signals, we harness the programmability of CRISPR-Cas12a to direct the nucleation and growth of a self-assembling synthetic polypeptide into virus-like particles (VLP) on specific DNA molecules. Positioning up to ten nuclease-dead Cas12a (dCas12a) proteins along a 48.5 kbp DNA template triggers particle growth and full DNA encapsidation at limiting polypeptide concentrations. Particle growth rate is further increased when dCas12a is dimerized with a polymerization silk-like domain. Such improved self-assembly efficiency allows for discrimination between cognate versus noncognate DNA templates by the synthetic polypeptide. CRISPR-guided VLPs will help to develop programmable bioinspired nanomaterials with applications in biotechnology as well as viromimetic scaffolds to improve our understanding of viral self-assembly.
    Keywords:  Cas12a; DNA curtain; assembly kinetics; virus-like particles
    DOI:  https://doi.org/10.1021/acs.nanolett.0c04640
  13. ACS Nano. 2021 Mar 16.
    Biological Mediator-Propelled Nanosweeper for Nonpharmaceutical Thrombus Therapy.
    Qingqing Deng, Lu Zhang, Wei Lv, Xuemeng Liu, Jinsong Ren, Xiaogang Qu.
      Traditional thrombolytic drugs offer limited outcomes due to short circulation half-life and low utilization. Herein, we have designed and constructed a biological mediator-propelled nanosweeper for highly efficient nonpharmaceutical thrombolysis and prevention of thrombus recurrence. Under the near-infrared light irradiation, the nanosweepers were activated to trigger nitric oxide (NO) release, which propelled the nanosweepers to penetrate deeply into the thrombus and resulted in enhanced site-pecific mechanical and photothermal thrombolysis. The experimental evidence confirmed that the ingenious nanosweeper displayed excellent site-specific thrombolytic efficacy even when compared with the clinical thrombolytic drug. In the meantime, as a biological mediator, the release of NO could effectively prevent thrombus recurrence in vivo. Overall, we anticipated that the nanosweeper would provide a promising strategy for the treatment of thrombi.
    Keywords:  biological mediator; nanosweeper; nitric oxide; nonpharmaceutical thrombolysis; recurrence of thrombus prevention
    DOI:  https://doi.org/10.1021/acsnano.0c09939
  14. Small. 2021 Mar 15. e2006110
    Janus Nanosheets with Face-Selective Molecular Recognition Properties from DNA-Peptide Conjugates.
    Shine K Albert, Sunghee Lee, Prasannavenkatesh Durai, Xiaole Hu, Byeongmoon Jeong, Keunwan Park, So-Jung Park.
      Chemical and functional anisotropy in Janus materials offer intriguing possibilities for constructing complex nanostructures and regulating chemical and biological reactions. Here, the authors report the fabrication of Janus nanosheets from molecular building blocks composed of two information-carrying biopolymers, DNA and peptides. Experimental and structural modeling studies reveal that DNA-peptide diblock conjugates assemble into Janus nanosheets with distinct DNA and peptide faces. The surprising level of structural control is attributed to the exclusive parallel β-sheet formation of phenylalanine-rich peptides. This approach is extended to triblock DNA1-peptide-DNA2 conjugates, which assemble into nanosheets presenting two different DNA on opposite faces. The Janus nanosheets with independently addressable faces are utilized to organize an enzyme pair for concerted enzymatic reactions, where enhanced catalytic activities are observed. These results demonstrate that the predictable and designable peptide interaction is a promising tool for creating Janus nanostructures with regio-selective and sequence-specific molecular recognition properties.
    Keywords:  DNA; Janus; nanosheets; peptides; self-assembly
    DOI:  https://doi.org/10.1002/smll.202006110
  15. Oncol Lett. 2021 Apr;21(4): 300
    miR-153 enhances the therapeutic effect of radiotherapy by targeting JAG1 in pancreatic cancer cells.
    Zhibin Zhao, Xiaoxue Shen, Dongli Zhang, Hongmei Xiao, Hongfang Kong, Bin Yang, Li Yang.
      Pancreatic cancer is one of the deadliest diseases, due to the lack of early symptoms and resistance to current therapies, including radiotherapy. However, the mechanisms of radioresistance in pancreatic cancer remain unknown. The present study explored the role of microRNA-153 (miR-153) in radioresistance of pancreatic cancer. It was observed that miR-153 was downregulated in pancreatic cancer and positively correlated with patient survival time. Using stably-infected pancreatic cancer cells that overexpressed miR-153 or miR-153 inhibitor, it was found that miR-153 overexpression sensitized pancreatic cancer cells to radiotherapy by inducing increased cell death and decreased colony formation, while cells transfected with the miR-153 inhibitor promoted radioresistance. Further investigation demonstrated that miR-153 promoted radiosensitivity by directly targeting jagged canonical Notch ligand 1 (JAG1). The addition of recombinant JAG1 protein in the cell cultures reversed the therapeutic effect of miR-153. The present study revealed a novel mechanism of radioresistance in pancreatic cancer and indicated that miR-153 may serve as a potential therapeutic target for radioresistance.
    Keywords:  cell apoptosis; jagged canonical Notch ligand 1; microRNA-153; pancreatic cancer; radioresistance
    DOI:  https://doi.org/10.3892/ol.2021.12561
  16. J Control Release. 2021 Mar 16. pii: S0168-3659(21)00129-2. [Epub ahead of print]
    Nano-ghosts: Novel biomimetic nano-vesicles for the delivery of antisense oligonucleotides.
    Jacopo Oieni, Andrea Lolli, Domenico D'Atri, Nicole Kops, Avner Yayon, Gerjo J V M van Osch, Marcelle Machluf.
      Antisense oligonucleotides (ASOs) carry an enormous therapeutic potential in different research areas, however, the lack of appropriate carriers for their delivery to the target tissues is hampering their clinical translation. The present study investigates the application of novel biomimetic nano-vesicles, Nano-Ghosts (NGs), for the delivery of ASOs to human mesenchymal stem cells (MSCs), using a microRNA inhibitor (antimiR) against miR-221 as proof-of-concept. The integration of this approach with a hyaluronic acid-fibrin (HA-FB) hydrogel scaffold is also studied, thus expanding the potential of NGs applications in regenerative medicine. The study shows robust antimiR encapsulation in the NGs using electroporation and the NGs ability to be internalized in MSCs and to deliver their cargo while avoiding endo-lysosomal degradation. This leads to rapid and strong knock-down of miR-221 in hMSCs in vitro, both in 2D and 3D hydrogel culture conditions (>90% and > 80% silencing efficiency, respectively). Finally, in vivo studies performed with an osteochondral defect model demonstrate the NGs ability to effectively deliver antimiR to endogenous cells. Altogether, these results prove that the NGs can operate as stand-alone system or as integrated platform in combination with scaffolds for the delivery of ASOs for a wide range of applications in drug delivery and regenerative medicine.
    Keywords:  Antisense oligonucleotides; Drug delivery; Nano-ghosts; Nanovesicles; Tissue engineering; microRNA
    DOI:  https://doi.org/10.1016/j.jconrel.2021.03.018
  17. Adv Mater. 2021 Mar 14. e2006237
    Programmable Design and Performance of Modular Magnetic Microswimmers.
    Christoph Pauer, Olivia du Roure, Julien Heuvingh, Tim Liedl, Joe Tavacoli.
      Synthetic biomimetic microswimmers are promising agents for in vivo healthcare and important frameworks to advance the understanding of locomotion strategies and collective motion at the microscopic scale. Nevertheless, constructing these devices with design flexibility and in large numbers remains a challenge. Here, a step toward meeting this challenge is taken by assembling such swimmers via the programmed shape and arrangement of superparamagnetic micromodules. The method's capacity for design flexibility is demonstrated through the assembly of a variety of swimmer architectures. On their actuation, strokes characterized by a balance of viscous and magnetic forces are found in all cases, but swimmers formed from a series of size-graded triangular modules swim quicker than more traditional designs comprising a circular "head" and a slender tail. Linking performance to design, rules are extracted informing the construction of a second-generation swimmer with a short tail and an elongated head optimized for speed. Its fast locomotion is attributed to a stroke that better breaks beating symmetry and an ability to beat fully with flex at high frequencies. Finally, production at scale is demonstrated through the assembly and swimming of a flock of the triangle-based architectures to reveal four types of swimmer couplings.
    Keywords:  collective behavior; microactuators; microswimmers; self-assembly
    DOI:  https://doi.org/10.1002/adma.202006237
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