bims-drudre Biomed News
on Targeted drug delivery and programmed release mechanisms
Issue of 2022–11–06
nine papers selected by
Ceren Kimna, Technical University of Munich
  1. Ligand-switchable nanoparticles resembling viral surface for sequential drug delivery and improved oral insulin therapy.
  2. Preparation of selective organ-targeting (SORT) lipid nanoparticles (LNPs) using multiple technical methods for tissue-specific mRNA delivery.
  3. Integrated Polymeric mRNA Vaccine without Inflammation Side-Effects for Cellular Immunity Mediated Cancer Therapy.
  4. Microneedle Array Encapsulated with Programmed DNA Hydrogels for Rapidly Sampling and Sensitively Sensing of Specific MicroRNA in Dermal Interstitial Fluid.
  5. Steering DNA Condensation on Engineered Nanointerfaces.
  6. Programmable self-regulated molecular buffers for precise sustained drug delivery.
  7. Microneedle Patches Loaded with Nanovesicles for Glucose Transporter-Mediated Insulin Delivery.
  8. A Light-Triggered Synthetic Nanopore for Controlling Molecular Transport Across Biological Membranes.
  9. Broad-Spectrum Virus Trapping with Heparan Sulfate-Modified DNA Origami Shells.
  1. Nat Commun. 2022 Nov 04. 13(1): 6649
    Ligand-switchable nanoparticles resembling viral surface for sequential drug delivery and improved oral insulin therapy.
    Tiantian Yang, Aohua Wang, Di Nie, Weiwei Fan, Xiaohe Jiang, Miaorong Yu, Shiyan Guo, Chunliu Zhu, Gang Wei, Yong Gan.
      Mutual interference between surface ligands on multifunctional nanoparticles remains a significant obstacle to achieving optimal drug-delivery efficacy. Here, we develop ligand-switchable nanoparticles which resemble viral unique surfaces, enabling them to fully display diverse functions. The nanoparticles are modified with a pH-responsive stretchable cell-penetrating peptide (Pep) and a liver-targeting moiety (Gal) (Pep/Gal-PNPs). Once orally administered, the acidic environments trigger the extension of Pep from surface in a virus-like manner, enabling Pep/Gal-PNPs to traverse intestinal barriers efficiently. Subsequently, Gal is exposed by Pep folding at physiological pH, thereby allowing the specific targeting of Pep/Gal-PNPs to the liver. As a proof-of-concept, insulin-loaded Pep/Gal-PNPs are fabricated which exhibit effective intestinal absorption and excellent hepatic deposition of insulin. Crucially, Pep/Gal-PNPs increase hepatic glycogen production by 7.2-fold, contributing to the maintenance of glucose homeostasis for effective diabetes management. Overall, this study provides a promising approach to achieving full potential of diverse ligands on multifunctional nanoparticles.
    DOI:  https://doi.org/10.1038/s41467-022-34357-8
  2. Nat Protoc. 2022 Oct 31.
    Preparation of selective organ-targeting (SORT) lipid nanoparticles (LNPs) using multiple technical methods for tissue-specific mRNA delivery.
    Xu Wang, Shuai Liu, Yehui Sun, Xueliang Yu, Sang M Lee, Qiang Cheng, Tuo Wei, Junyu Gong, Joshua Robinson, Di Zhang, Xizhen Lian, Pratima Basak, Daniel J Siegwart.
      A new methodology termed selective organ targeting (SORT) was recently developed that enables controllable delivery of nucleic acids to target tissues. SORT lipid nanoparticles (LNPs) involve the inclusion of SORT molecules that accurately tune delivery to the liver, lungs and spleen of mice after intravenous administration. Nanoparticles can be engineered to target specific cells and organs in the body by passive, active and endogenous targeting mechanisms that require distinct design criteria. SORT LNPs are modular and can be prepared using scalable, synthetic chemistry and established engineering formulation methods. This protocol provides detailed procedures, including the synthesis of a representative ionizable cationic lipid, preparation of multiple classes of SORT LNPs by pipette, vortex and microfluidic mixing methods, physical characterization, and in vitro/in vivo mRNA delivery evaluation. Depending on the scale of the experiments, the synthesis of the ionizable lipid requires 4-6 d; LNPs can be formulated within several hours; LNP characterization can be completed in 2-4 h; and in vitro/in vivo evaluation studies require 1-14 d, depending on the design and application. Our strategy offers a versatile and practical method for rationally designing nanoparticles that accurately target specific organs. The SORT LNPs generated as described in this protocol can therefore be applied to multiple classes of LNP systems for therapeutic nucleic acid delivery and facilitate the development of protein replacement and genetic medicines in target tissues. This protocol does not require specific expertise, is modular to various lipids within defined physicochemical classes, and should be accomplishable by researchers from various backgrounds.
    DOI:  https://doi.org/10.1038/s41596-022-00755-x
  3. Adv Mater. 2022 Nov 03. e2207471
    Integrated Polymeric mRNA Vaccine without Inflammation Side-Effects for Cellular Immunity Mediated Cancer Therapy.
    Pei Huang, Lingsheng Jiang, Hui Pan, Lingwen Ding, Bo Zhou, Mengyao Zhao, Jianhua Zou, Benhao Li, Meiwei Qi, Hongzhang Deng, Yongfeng Zhou, Xiaoyuan Chen.
      Among the few available mRNA delivery vehicles, lipid nanoparticle (LNP) is the most clinically advanced one but requires cumbersome four components and suffers from inflammation-related side effects which should be minimized for safety. Yet, a certain level of proinflammatory responses and innate immune activation is required to evoke T-cell immunity for mRNA cancer vaccination. To address these issues and develop potent yet low-inflammatory mRNA cancer vaccine vectors, we synthesized a series of alternating copolymers "PHTA" featured with ortho-hydroxy tertiary amine (HTA) repeating units for mRNA delivery, which can play triple roles of condensing mRNA, enhancing the polymeric nanoparticle (PNP) stability, and prolonging circulation time. Unlike the LNPs exhibiting high levels of inflammation, the PHTA-based PNPs showed negligible inflammatory side effects in vivo. Importantly, the top candidate PHTA-C18 enabled successful mRNA cancer vaccine delivery in vivo and led to a robust CD8+ T cell-mediated antitumor cellular immunity. Such PHTA-based integrated PNP provides a potential approach for establishing mRNA cancer vaccines with good inflammatory safety profiles. This article is protected by copyright. All rights reserved.
    Keywords:  alternating copolymer; cancer immunotherapy; cellular immunity; mRNA cancer vaccine; polymer nanoparticles
    DOI:  https://doi.org/10.1002/adma.202207471
  4. ACS Nano. 2022 Nov 03.
    Microneedle Array Encapsulated with Programmed DNA Hydrogels for Rapidly Sampling and Sensitively Sensing of Specific MicroRNA in Dermal Interstitial Fluid.
    Qiqi Yang, Yeyu Wang, Tengfei Liu, Chaoxiong Wu, Jinze Li, Jiale Cheng, Wei Wei, Fan Yang, Liping Zhou, Yufan Zhang, Shuangshuang Yang, Haifeng Dong.
      Author: Please verify that the changes made to improve the English still retain your original meaning.Detection of microRNA (miRNA) in dermal interstitial fluid (ISF) has emerged as clinically useful in health status monitoring. However, it remains a great challenge owing to the difficult sampling and low abundance. Here, we report a DNA hydrogel microneedles (MNs) array to realize rapid enrichment and sensitive detection of miRNA in ISF. The MNs' patch consists of methacrylate hyaluronic acid (MeHA) equipped with a smart DNA circuit hydrogels' system (MeHA/DNA), in which an appropriate miRNA input enables triggering a cascading toehold-mediated DNA displacement reaction to catalytically cleave cross-linking points to generate amplified fluorescence (FL) for miRNA detection. The MeHA/DNA-MNs patch with high mechanical strength can extract adequate ISF in a short time (0.97 ± 0.2 mg in 5 min) in vivo because of its supreme water affinity. Additionally, the cascading toehold-mediated DNA displacement signal amplification reaction allows for sensitive detection of the low-abundant miRNAs down to 241.56 pM. The DNA hydrogels' MNs present potential for minimally invasive personalized diagnosis and real-time health monitoring in clinical applications.
    Keywords:  DNA hydrogels; Interstitial fluid; Methacrylated hyaluronic acid; MicroRNA detection; Microneedles
    DOI:  https://doi.org/10.1021/acsnano.2c06261
  5. Nano Lett. 2022 Oct 31.
    Steering DNA Condensation on Engineered Nanointerfaces.
    Nuo Chen, Yueliang Wang, Xiaojun Song, Yanjuan Li, Zhaoxiang Deng.
      DNA has received increasing attention in nanotechnology due to its ability to fold into prescribed structures. Different from the commonly adopted base-pairing strategy, an emerging class of amorphous DNA materials are formed by DNA's abiological interactions. Despite the great successes, a lack of nanoscale nucleation/growth control disables more advanced considerations. This work aims at harnessing the heterogeneous nucleation of metal-ion-glued DNA condensates on nanointerfaces. Upon unveiling key orthogonal factors including solution pH, ionic cross-linkers, and surface functionalities, chemically programmable DNA condensation on nanoparticle seeds is achieved, resembling a famous Stöber process for silica coating. The nucleation rules discovered on individual nanoseeds can be passed on to their dimeric assemblies, where broken spherical symmetry and the existence of interparticle gaps help a regiospecific DNA gelation. The steerable DNA condensation, and the multifunctions from DNA, metal ions, and nanocores, hold a great promise in noncanonical DNA nanotechnology toward novel applications.
    Keywords:  DNA condensation; amorphous material; metal ion; nanoparticle; nucleation
    DOI:  https://doi.org/10.1021/acs.nanolett.2c03051
  6. Nat Commun. 2022 Nov 02. 13(1): 6504
    Programmable self-regulated molecular buffers for precise sustained drug delivery.
    Arnaud Desrosiers, Rabeb Mouna Derbali, Sami Hassine, Jérémie Berdugo, Valérie Long, Dominic Lauzon, Vincent De Guire, Céline Fiset, Luc DesGroseillers, Jeanne Leblond Chain, Alexis Vallée-Bélisle.
      Unlike artificial nanosystems, biological systems are ideally engineered to respond to their environment. As such, natural molecular buffers ensure precise and quantitative delivery of specific molecules through self-regulated mechanisms based on Le Chatelier's principle. Here, we apply this principle to design self-regulated nucleic acid molecular buffers for the chemotherapeutic drug doxorubicin and the antimalarial agent quinine. We show that these aptamer-based buffers can be programmed to maintain any specific desired concentration of free drug both in vitro and in vivo and enable the optimization of the chemical stability, partition coefficient, pharmacokinetics and biodistribution of the drug. These programmable buffers can be built from any polymer and should improve patient therapeutic outcome by enhancing drug activity and minimizing adverse effects and dosage frequency.
    DOI:  https://doi.org/10.1038/s41467-022-33491-7
  7. ACS Nano. 2022 Nov 02.
    Microneedle Patches Loaded with Nanovesicles for Glucose Transporter-Mediated Insulin Delivery.
    Qian Chen, Zhisheng Xiao, Chao Wang, Guojun Chen, Yuqi Zhang, Xudong Zhang, Xiao Han, Jinqiang Wang, Xiao Ye, Mark R Prausnitz, Song Li, Zhen Gu.
      Glucose-responsive insulin delivery systems that mimic insulin secretion activity in the pancreas show great potential to improve clinical therapeutic outcomes for people with type 1 and advanced type 2 diabetes. Here, we report a glucose-responsive insulin delivery microneedle (MN) array patch that is loaded with red blood cell (RBC) vesicles or liposome nanoparticles containing glucose transporters (GLUTs) bound with glucosamine-modified insulin (Glu-Insulin). In hyperglycemic conditions, high concentrations of glucose in interstitial fluid can replace Glu-Insulin via a competitive interaction with GLUT, leading to a quick release of Glu-Insulin and subsequent regulation of blood glucose (BG) levels in vivo. To prolong the effective glucose-responsive insulin release from MNs, additional free Glu-Insulin, which serves as "stored insulin", is loaded after RBC vesicles or liposome nanoparticles bound with Glu-Insulin. In the streptozotocin (STZ)-induced type 1 diabetic mouse model, this smart GLUT-based insulin patch can effectively control BG levels without causing hypoglycemia.
    Keywords:  diabetes; drug delivery; glucose transporter; glucose-responsive; microneedles
    DOI:  https://doi.org/10.1021/acsnano.2c05687
  8. Angew Chem Int Ed Engl. 2022 Nov 01.
    A Light-Triggered Synthetic Nanopore for Controlling Molecular Transport Across Biological Membranes.
    Daniel Offenbartl-Stiegert, Alexia Rottensteiner, Adam Dorey, Stefan Howorka.
      Controlling biological molecular processes with light is of high interest in biological research and biomedicine, as light allows precise and selective activation in a non-invasive and non-toxic manner. A molecular process benefitting from light control is the transport of cargo across biological membranes, which is conventionally achieved by membrane-puncturing barrel-shaped nanopores. Yet, there is considerable interest to construct more complex gated pores. Here, we pioneer a synthetic light-gated nanostructure which controls transport across membranes via a controllable lid. The light-triggered nanopore is self-assembled from six pore DNA strands and a lid strand carrying light-switchable azobenzene molecules. Exposure to light opens the pore to allow small-molecule transport across membranes. Our light-triggered pore advances biomimetic chemistry and DNA nanotechnology and may be used in biotechnology, biosensing, targeted drug release, or synthetic cells.
    Keywords:  DNA nanotechnology * membranes * nanopores * photoswitch
    DOI:  https://doi.org/10.1002/anie.202210886
  9. ACS Nano. 2022 Nov 02.
    Broad-Spectrum Virus Trapping with Heparan Sulfate-Modified DNA Origami Shells.
    Alba Monferrer, Jessica A Kretzmann, Christian Sigl, Pia Sapelza, Anna Liedl, Barbara Wittmann, Hendrik Dietz.
      Effective broadband antiviral platforms that can act on existing viruses and viruses yet to emerge are not available, creating a need to explore treatment strategies beyond the trodden paths. Here, we report virus-encapsulating DNA origami shells that achieve broadband virus trapping properties by exploiting avidity and a widespread background affinity of viruses to heparan sulfate proteoglycans (HSPG). With a calibrated density of heparin and heparan sulfate (HS) derivatives crafted to the interior of DNA origami shells, we could encapsulate adeno, adeno-associated, chikungunya, dengue, human papilloma, noro, polio, rubella, and SARS-CoV-2 viruses or virus-like particles, in one and the same HS-functionalized shell system. Additional virus-type-specific binders were not needed for the trapping. Depending on the relative dimensions of shell to virus particles, multiple virus particles may be trapped per shell, and multiple shells can cover the surface of clusters of virus particles. The steric occlusion provided by the heparan sulfate-coated DNA origami shells can prevent viruses from further interactions with receptors, possibly including those found on cell surfaces.
    Keywords:  DNA origami; antiviral; broad-spectrum; heparan sulfate; heparin; virus-like particles
    DOI:  https://doi.org/10.1021/acsnano.1c11328
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