bims-drudre Biomed News
on Targeted drug delivery and programmed release mechanisms
Issue of 2021–06–06
thirteen papers selected by
Ceren Kimna, Technical University of Munich
  1. Base editing of haematopoietic stem cells rescues sickle cell disease in mice.
  2. Complex Metal Nanostructures with Programmable Shapes from Simple DNA Building Blocks.
  3. Formulation of a Composite Nasal Spray Enabling Enhanced Surface Coverage and Prophylaxis of SARS-COV-2.
  4. Fibrinogen-mimicking, multiarm nanovesicles for human thrombus-specific delivery of tissue plasminogen activator and targeted thrombolytic therapy.
  5. miR-506-loaded gelatin nanospheres target PENK and inactivate the ERK/Fos signaling pathway to suppress triple-negative breast cancer aggressiveness.
  6. Nanoscale FasL Organization on DNA Origami to Decipher Apoptosis Signal Activation in Cells.
  7. Ultrafast self-gelling powder mediates robust wet adhesion to promote healing of gastrointestinal perforations.
  8. Genetically Encoding Ultrastable Virus-like Particles Encapsulating Functional DNA Nanostructures in Living Bacteria.
  9. The current landscape of nucleic acid therapeutics.
  10. Photoacoustic Force-Guided Precise and Fast Delivery of Nanomedicine with Boosted Therapeutic Efficacy.
  11. Molecular Engineering of High-Performance Aggregation-Induced Emission Photosensitizers to Boost Cancer Theranostics Mediated by Acid-Triggered Nucleus-Targeted Nanovectors.
  12. Intravenous Delivery of Lung-Targeted Nanofibers for Pulmonary Hypertension in Mice.
  13. Shear stress and ROS-responsive biomimetic micelles for atherosclerosis via ROS consumption.
  1. Nature. 2021 Jun 02.
    Base editing of haematopoietic stem cells rescues sickle cell disease in mice.
    Gregory A Newby, Jonathan S Yen, Kaitly J Woodard, Thiyagaraj Mayuranathan, Cicera R Lazzarotto, Yichao Li, Heather Sheppard-Tillman, Shaina N Porter, Yu Yao, Kalin Mayberry, Kelcee A Everette, Yoonjeong Jang, Christopher J Podracky, Elizabeth Thaman, Christophe Lechauve, Akshay Sharma, Jordana M Henderson, Michelle F Richter, Kevin T Zhao, Shannon M Miller, Tina Wang, Luke W Koblan, Anton P McCaffrey, John F Tisdale, Theodosia A Kalfa, Shondra M Pruett-Miller, Shengdar Q Tsai, Mitchell J Weiss, David R Liu.
      Sickle cell disease (SCD) is caused by a mutation in the β-globin gene HBB1. We used a custom adenine base editor (ABE8e-NRCH)2,3 to convert the SCD allele (HBBS) into Makassar β-globin (HBBG), a non-pathogenic variant4,5. Ex vivo delivery of mRNA encoding the base editor with a targeting guide RNA into haematopoietic stem and progenitor cells (HSPCs) from patients with SCD resulted in 80% conversion of HBBS to HBBG. Sixteen weeks after transplantation of edited human HSPCs into immunodeficient mice, the frequency of HBBG was 68% and hypoxia-induced sickling of bone marrow reticulocytes had decreased fivefold, indicating durable gene editing. To assess the physiological effects of HBBS base editing, we delivered ABE8e-NRCH and guide RNA into HSPCs from a humanized SCD mouse6 and then transplanted these cells into irradiated mice. After sixteen weeks, Makassar β-globin represented 79% of β-globin protein in blood, and hypoxia-induced sickling was reduced threefold. Mice that received base-edited HSPCs showed near-normal haematological parameters and reduced splenic pathology compared to mice that received unedited cells. Secondary transplantation of edited bone marrow confirmed that the gene editing was durable in long-term haematopoietic stem cells and showed that HBBS-to-HBBG editing of 20% or more is sufficient for phenotypic rescue. Base editing of human HSPCs avoided the p53 activation and larger deletions that have been observed following Cas9 nuclease treatment. These findings point towards a one-time autologous treatment for SCD that eliminates pathogenic HBBS, generates benign HBBG, and minimizes the undesired consequences of double-strand DNA breaks.
    DOI:  https://doi.org/10.1038/s41586-021-03609-w
  2. Adv Mater. 2021 Jun 04. e2100381
    Complex Metal Nanostructures with Programmable Shapes from Simple DNA Building Blocks.
    Jingjing Ye, Olha Aftenieva, Türkan Bayrak, Archa Jain, Tobias A F König, Artur Erbe, Ralf Seidel.
      Advances in DNA nanotechnology allow the design and fabrication of highly complex DNA structures, uisng specific programmable interactions between smaller nucleic acid building blocks. To convey this concept to the fabrication of metallic nanoparticles, an assembly platform is developed based on a few basic DNA structures that can serve as molds. Programming specific interactions between these elements allows the assembly of mold superstructures with a range of different geometries. Subsequent seeded growth of gold within the mold cavities enables the synthesis of complex metal structures including tightly DNA-caged particles, rolling-pin- and dumbbell-shaped particles, as well as T-shaped and loop particles with high continuity. The method further supports the formation of higher-order assemblies of the obtained metal geometries. Based on electrical and optical characterizations, it is expected that the developed platform is a valuable tool for a self-assembly-based fabrication of nanoelectronic and nanooptic devices.
    Keywords:  DNA origami; DNA templating; gold nanoparticles; seeded growth; shape programming
    DOI:  https://doi.org/10.1002/adma.202100381
  3. Adv Mater. 2021 May 31. e2008304
    Formulation of a Composite Nasal Spray Enabling Enhanced Surface Coverage and Prophylaxis of SARS-COV-2.
    Richard J A Moakes, Scott P Davies, Zania Stamataki, Liam M Grover.
      Airborne pathogens pose high risks in terms of both contraction and transmission within the respiratory pathways, particularly the nasal region. However, there is little in the way of adequate intervention that can protect an individual or prevent further spread. This study reports on a nasal formulation with the capacity to combat such challenges, focusing on severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). Formulation of a polysaccharide-based spray, known for its mucoadhesive properties, is undertaken and it is characterized for its mechanical, spray distribution, and antiviral properties. The ability to engineer key mechanical characteristics such as dynamic yield stresses and high coverage is shown, through systematic understanding of the composite mixture containing both gellan and λ-carrageenan. Furthermore, the spray systems demonstrate highly potent capacities to prevent SARS-CoV-2 infection in Vero cells, resulting in complete inhibition when either treating, the cells, or the virus, prior to challenging for infection. From this data, a mechanism for both prophylaxis and prevention is proposed; where entrapment within a polymeric coating sterically blocks virus uptake into the cells, inactivating the virus, and allowing clearance within the viscous medium. As such, a fully preventative spray is formulated, targeted at protecting the lining of the upper respiratory pathways against SARS-CoV-2.
    Keywords:  COVID-19; SARS-CoV-2; carrageenan; formulation engineering; nasal sprays
    DOI:  https://doi.org/10.1002/adma.202008304
  4. Sci Adv. 2021 Jun;pii: eabf9033. [Epub ahead of print]7(23):
    Fibrinogen-mimicking, multiarm nanovesicles for human thrombus-specific delivery of tissue plasminogen activator and targeted thrombolytic therapy.
    Yu Huang, Boram Gu, Isabelle I Salles-Crawley, Kirk A Taylor, Li Yu, Jie Ren, Xuhan Liu, Michael Emerson, Colin Longstaff, Alun D Hughes, Simon A Thom, Xiao Yun Xu, Rongjun Chen.
      Clinical use of tissue plasminogen activator (tPA) in thrombolytic therapy is limited by its short circulation time and hemorrhagic side effects. Inspired by fibrinogen binding to activated platelets, we report a fibrinogen-mimicking, multiarm nanovesicle for thrombus-specific tPA delivery and targeted thrombolysis. This biomimetic system is based on the lipid nanovesicle coated with polyethylene glycol (PEG) terminally conjugated with a cyclic RGD (cRGD) peptide. Our experiments with human blood demonstrated its highly selective binding to activated platelets and efficient tPA release at a thrombus site under both static and physiological flow conditions. Its clot dissolution time in a microfluidic system was comparable to that of free tPA. Furthermore, we report a purpose-built computational model capable of simulating targeted thrombolysis of the tPA-loaded nanovesicle and with a potential in predicting the dynamics of thrombolysis in physiologically realistic scenarios. This combined experimental and computational work presents a promising platform for development of thrombolytic nanomedicines.
    DOI:  https://doi.org/10.1126/sciadv.abf9033
  5. Mol Carcinog. 2021 Jun 01.
    miR-506-loaded gelatin nanospheres target PENK and inactivate the ERK/Fos signaling pathway to suppress triple-negative breast cancer aggressiveness.
    Xin-Li Liu, Wen-Jing Liu, Qiang Chen, Jie Liu, Chang-Qing Yang, Ge Zhang, Shi-Long Zhang, Wei-Hong Guo, Jing-Bao Li, Gang Zhao, Da-Chuan Yin, Chen-Yan Zhang.
      Triple-negative breast cancer (TNBC) is the most malignant subtype of breast cancer. Some microRNAs (miRNAs) were abnormally expressed in TNBC, and they are closely related to the occurrence and progression of TNBC. Here, we found that miR-506 was significantly downregulated in TNBC and relatively lower miR-506 expression predicted a poorer prognosis. Moreover, we found that miR-506 could inhibit MDA-MB-231 cell viability, colony formation, migration, and invasion, and suppress the ERK/Fos oncogenic signaling pathway through upregulating its direct target protein proenkephalin (PENK). Therefore, miR-506 was proposed as a nucleic acid drug for TNBC therapy. However, miRNA is unstable in vivo, which limiting its application as a therapeutic drug via conventional oral or injected therapies. Here, a gelatin nanosphere (GN) delivery system was applied for the first time to load exogenous miRNA. Exogenous miR-506 mimic was loaded on GNs and injected into the in situ TNBC animal model, and the miR-506 could achieve sustained and controlled release. The results confirmed that overexpression of miR-506 and PENK in vivo through loading on GNs inhibited in situ triple-negative breast tumor growth and metastasis significantly in the xenograft model. Moreover, we indicated that the ERK/Fos signaling pathway was intensively inactivated after overexpression of miR-506 and PENK both in vitro and in vivo, which was further validated by the ERK1/2-specific inhibitor SCH772984. In conclusion, this study demonstrates that miR-506-loaded GNs have great potential in anti-TNBC aggressiveness therapy.
    Keywords:  PENK; aggressiveness; gelatin nanospheres; miR-506; triple-negative breast cancer
    DOI:  https://doi.org/10.1002/mc.23310
  6. Small. 2021 May 31. e2101678
    Nanoscale FasL Organization on DNA Origami to Decipher Apoptosis Signal Activation in Cells.
    Ricarda M L Berger, Johann M Weck, Simon M Kempe, Oliver Hill, Tim Liedl, Joachim O Rädler, Cornelia Monzel, Amelie Heuer-Jungemann.
      Cell signaling is initiated by characteristic protein patterns in the plasma membrane, but tools to decipher their molecular organization and activation are hitherto lacking. Among the well-known signaling pattern is the death inducing signaling complex with a predicted hexagonal receptor architecture. To probe this architecture, DNA origami-based nanoagents with nanometer precise arrangements of the death receptor ligand FasL are introduced and presented to cells. Mimicking different receptor geometries, these nanoagents act as signaling platforms inducing fastest time-to-death kinetics for hexagonal FasL arrangements with 10 nm inter-molecular spacing. Compared to naturally occurring soluble FasL, this trigger is faster and 100× more efficient. Nanoagents with different spacing, lower FasL number or higher coupling flexibility impede signaling. The results present DNA origami as versatile signaling scaffolds exhibiting unprecedented control over molecular number and geometry. They define molecular benchmarks in apoptosis signal initiation and constitute a new strategy to drive particular cell responses.
    Keywords:  DNA origami; FasL/FasR; cell apoptosis; ligand-receptor interactions; signaling complex
    DOI:  https://doi.org/10.1002/smll.202101678
  7. Sci Adv. 2021 Jun;pii: eabe8739. [Epub ahead of print]7(23):
    Ultrafast self-gelling powder mediates robust wet adhesion to promote healing of gastrointestinal perforations.
    Xin Peng, Xianfeng Xia, Xiayi Xu, Xuefeng Yang, Boguang Yang, Pengchao Zhao, Weihao Yuan, Philip Wai Yan Chiu, Liming Bian.
      Achieving strong adhesion of bioadhesives on wet tissues remains a challenge and an acute clinical demand because of the interfering interfacial water and limited adhesive-tissue interactions. Here we report a self-gelling and adhesive polyethyleneimine and polyacrylic acid (PEI/PAA) powder, which can absorb interfacial water to form a physically cross-linked hydrogel in situ within 2 seconds due to strong physical interactions between the polymers. Furthermore, the physically cross-linked polymers can diffuse into the substrate polymeric network to enhance wet adhesion. Superficial deposition of PEI/PAA powder can effectively seal damaged porcine stomach and intestine despite excessive mechanical challenges and tissue surface irregularities. We further demonstrate PEI/PAA powder as an effective sealant to enhance the treatment outcomes of gastric perforation in a rat model. The strong wet adhesion, excellent cytocompatibility, adaptability to fit complex sites, and easy synthesis of PEI/PAA powder make it a promising bioadhesive for numerous biomedical applications.
    DOI:  https://doi.org/10.1126/sciadv.abe8739
  8. ACS Synth Biol. 2021 Jun 02.
    Genetically Encoding Ultrastable Virus-like Particles Encapsulating Functional DNA Nanostructures in Living Bacteria.
    Shai Zilberzwige-Tal, Dan Mark Alon, Danielle Gazit, Shahar Zachariah, Amit Hollander, Ehud Gazit, Johann Elbaz.
      DNA nanotechnology is leading the field of in vitro molecular-scale device engineering, accumulating to a dazzling array of applications. However, while DNA nanostructures' function is robust under in vitro settings, their implementation in real-world conditions requires overcoming their rapid degradation and subsequent loss of function. Viruses are sophisticated supramolecular assemblies, able to protect their nucleic acid content in inhospitable biological environments. Inspired by this natural ability, we engineered in vitro and in vivo technologies, enabling the encapsulation and protection of functional DNA nanostructures inside MS2 bacteriophage virus-like particles (VLPs). We demonstrate the ssDNA-VLPs nanocomposites' (NCs) abilities to encapsulate single-stranded-DNA (ssDNA) in a variety of sizes (200-1500 nucleotides (nt)), sequences, and structures while retaining their functionality. Moreover, by exposing these NCs to hostile biological conditions, such as human blood serum, we exhibit that the VLPs serve as an excellent protective shell. These engineered NCs pose critical properties that are yet unattainable by current fabrication methods.
    Keywords:  DNA nanostructures; MS2 VLPs; aptamers; nanocomposites; ssDNA encapsulation
    DOI:  https://doi.org/10.1021/acssynbio.0c00586
  9. Nat Nanotechnol. 2021 May 31.
    The current landscape of nucleic acid therapeutics.
    Jayesh A Kulkarni, Dominik Witzigmann, Sarah B Thomson, Sam Chen, Blair R Leavitt, Pieter R Cullis, Roy van der Meel.
      The increasing number of approved nucleic acid therapeutics demonstrates the potential to treat diseases by targeting their genetic blueprints in vivo. Conventional treatments generally induce therapeutic effects that are transient because they target proteins rather than underlying causes. In contrast, nucleic acid therapeutics can achieve long-lasting or even curative effects via gene inhibition, addition, replacement or editing. Their clinical translation, however, depends on delivery technologies that improve stability, facilitate internalization and increase target affinity. Here, we review four platform technologies that have enabled the clinical translation of nucleic acid therapeutics: antisense oligonucleotides, ligand-modified small interfering RNA conjugates, lipid nanoparticles and adeno-associated virus vectors. For each platform, we discuss the current state-of-the-art clinical approaches, explain the rationale behind its development, highlight technological aspects that facilitated clinical translation and provide an example of a clinically relevant genetic drug. In addition, we discuss how these technologies enable the development of cutting-edge genetic drugs, such as tissue-specific nucleic acid bioconjugates, messenger RNA and gene-editing therapeutics.
    DOI:  https://doi.org/10.1038/s41565-021-00898-0
  10. Adv Sci (Weinh). 2021 Jun 03. e2100228
    Photoacoustic Force-Guided Precise and Fast Delivery of Nanomedicine with Boosted Therapeutic Efficacy.
    Jun Wang, Tingting Li, Jen-Shyang Ni, Heng Guo, Tianyi Kang, Zeshun Li, Menglei Zha, Songbo Lu, Chen Zhang, Weizhi Qi, Lei Xi, Kai Li.
      Precise and efficient delivery of nanomedicine to the target site has remained as a major roadblock in advanced cancer treatment. Here, a novel photoacoustic force (PAF)-guided nanotherapeutic system is reported based on a near-infrared (NIR)-absorbing semiconducting polymer (SP), showing significantly improved tumor accumulation and deep tissue penetration for enhanced phototherapeutic efficacy. The accumulation of nanoparticles in 4T1 tumor-bearing mice induced by the PAF strategy displays a fivefold enhancement in comparison with that of the traditional passive targeting pathway, in a significantly shortened time (45 min vs 24 h) with an enhanced penetration depth in tumors. Additionally, a tumor-bearing mouse model is rationally designed to unveil the mechanism, indicating that the nanoparticles enter solid tumors through enhanced transportation across blood vessel barriers via both inter-endothelial gaps and active trans-endothelial pathways. This process is specifically driven by PAF generated from the nanoparticles under NIR laser irradiation. The study thus demonstrates a new nanotherapeutic strategy with low dose, enhanced delivery efficiency in tumor, and boosted therapeutic efficacy, opening new doors for designing novel nanocarriers.
    Keywords:  nanomedicine delivery; photoacoustic force; photodynamic therapy; photothermal therapy; semiconducting polymer
    DOI:  https://doi.org/10.1002/advs.202100228
  11. ACS Nano. 2021 Jun 02.
    Molecular Engineering of High-Performance Aggregation-Induced Emission Photosensitizers to Boost Cancer Theranostics Mediated by Acid-Triggered Nucleus-Targeted Nanovectors.
    Zhijun Zhang, Wenhan Xu, Peihong Xiao, Miaomiao Kang, Dingyuan Yan, Haifei Wen, Nan Song, Dong Wang, Ben Zhong Tang.
      Phototheranostics involving both fluorescence imaging and photodynamic therapy has been recognized to be potentially powerful for cancer treatment by virtue of various intrinsic advantages. However, the state-of-the-art materials in this area are still far from ideal toward practical applications, ascribed to their respective and collective drawbacks, such as inefficient imaging quality, inferior reactive oxygen species (ROS) production, the lack of subcellular-targeting capability, and dissatisfactory delivery. In this paper, these shortcomings are successfully addressed through the integration of finely engineered photosensitizers with aggregation-induced emission (AIE) features and well tailored nanocarrier systems. The yielded AIE NPs simultaneously exhibit broad absorption in the visible-light region, bright near-infrared fluorescence emission, high ROS generation, as well as tumor lysosomal acidity-activated and nucleus-targeted delivery functions, making them promising for precise and efficient phototheranostics. Both in vitro and in vivo evaluations show that the presented nanotheranostic systems bearing good photostability and appreciable biosecurity perform well in fluorescence imaging-guided photodynamic cancer therapy. This study thus not only extends the application scopes of AIE nanomaterials but also offers useful insights into constructing advanced cancer phototheranostics.
    Keywords:  aggregation-induced emission; high photosensitivity; molecular engineering; near-infrared emission; nucleus-targeted theranostics
    DOI:  https://doi.org/10.1021/acsnano.1c03700
  12. Adv Healthc Mater. 2021 Jun 01. e2100302
    Intravenous Delivery of Lung-Targeted Nanofibers for Pulmonary Hypertension in Mice.
    Kathleen Marulanda, Alexandra Mercel, David C Gillis, Kui Sun, Maria Gambarian, Joshua Roark, Jenna Weiss, Nick D Tsihlis, Mark R Karver, S Ruben Centeno, Erica B Peters, Tristan D Clemons, Samuel I Stupp, Sean E McLean, Melina R Kibbe.
      Pulmonary hypertension is a highly morbid disease with no cure. Available treatments are limited by systemic adverse effects due to non-specific biodistribution. Self-assembled peptide amphiphile (PA) nanofibers are biocompatible nanomaterials that can be modified to recognize specific biological markers to provide targeted drug delivery and reduce off-target toxicity. Here, PA nanofibers that target the angiotensin I-converting enzyme and the receptor for advanced glycation end-products (RAGE) are developed, as both proteins are overexpressed in the lung with pulmonary hypertension. It is demonstrated that intravenous delivery of RAGE-targeted nanofibers containing the targeting epitope LVFFAED (LVFF) significantly accumulated within the lung in a chronic hypoxia-induced pulmonary hypertension mouse model. Using 3D light sheet fluorescence microscopy, it is shown that LVFF nanofiber localization is specific to the diseased pulmonary tissue with immunofluorescence analysis demonstrating colocalization of the targeted nanofiber to RAGE in the hypoxic lung. Furthermore, biodistribution studies show that significantly more LVFF nanofibers localized to the lung compared to major off-target organs. Targeted nanofibers are retained within the pulmonary tissue for 24 h after injection. Collectively, these data demonstrate the potential of a RAGE-targeted nanomaterial as a drug delivery platform to treat pulmonary hypertension.
    Keywords:  nanofibers; peptide amphiphiles; pulmonary hypertension; targeted drug delivery
    DOI:  https://doi.org/10.1002/adhm.202100302
  13. Mater Sci Eng C Mater Biol Appl. 2021 Jul;pii: S0928-4931(21)00303-9. [Epub ahead of print]126 112164
    Shear stress and ROS-responsive biomimetic micelles for atherosclerosis via ROS consumption.
    Meili Shen, Hongli Li, Shunyu Yao, Xiaodong Wu, Shun Liu, Qingbiao Yang, Yanjiao Zhang, Jianshi Du, Shaolong Qi, Yapeng Li.
      Reactive oxygen species (ROS) are well-known important initiating factors required for atherosclerosis formation, which leads to endothelial dysfunction and plaque formation. Most of the existing antithrombotic therapies use ROS-responsive drug delivery systems, which have a certain therapeutic effect but cannot eliminate excess ROS. Therefore, the atherosclerosis cannot be treated from the source. Moreover, nanoparticles are easily cleared by the immune system during blood circulation, which is not conducive to long-term circulation. In this study, we developed an intelligent response system that could simultaneously respond to ROS and the shear stress microenvironment of atherosclerotic plaques. This system was formed by red blood cells (RBCs) and simvastatin-loaded micelles (SV MC). The micelles consisted of poly(glycidyl methacrylate)-polypropylene sulfide (PGED-PPS). The hydrophobic PPS could react with excess ROS to become hydrophilic, which forced the micelle rupture, resulting in drug release. Most importantly, PPS could also significantly deplete the ROS level, realizing the synergistic treatment of atherosclerosis with drugs and materials. The positively charged SV MC and negatively charged RBCs were self-assembled through electrostatic adsorption to obtain SV MC@RBCs. The SV MC@RBCs could respond to the high shear stress at the atherosclerotic plaque, and the shear stress induced SV MC desorption from the RBC surface. Using biomimetic methods to evade the SV MC@RBCs elimination by the immune system and to reduce the ROS plays a vital role in improving atherosclerosis treatment. The results of in vitro and in vivo experiments showed that SV MC@RBCs could effectively treat atherosclerosis. Moreover, not only does the SV MC@RBCs system avoid the risk of bleeding, but it also has excellent in vivo safety. The study results indicate that the SV MC@RBCs system is a promising therapeutic nanomedicine for treating ROS-related diseases.
    Keywords:  Atherosclerosis; Reactive oxygen species; Red blood cells; Shear stress; Simvastatin
    DOI:  https://doi.org/10.1016/j.msec.2021.112164
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