bims-drudre 2022-09-04 papers

bims-drudre

Biomed News

on Targeted drug delivery and programmed release mechanisms

Issue of 2022–09–04
nine papers selected by
Ceren Kimna, Technical University of Munich

Engineering Lipid Nanoparticles for Enhanced Intracellular Delivery of mRNA through Inhalation.
A proposed mathematical description of in vivo nanoparticle delivery.
Simulations of DNA-Origami Self-Assembly Reveal Design-Dependent Nucleation Barriers.
Programmable Assembly of Amphiphilic DNA through Controlled Cholesterol Stacking.
Bacteria loaded with glucose polymer and photosensitive ICG silicon-nanoparticles for glioblastoma photothermal immunotherapy.
Abalone-Inspired Adhesive and Photo-Responsive Microparticle Delivery Systems for Periodontal Drug Therapy.
Enhanced Intracellular Transcytosis of Nanoparticles by Degrading Extracellular Matrix for Deep Tissue Radiotherapy of Pancreatic Adenocarcinoma.
Polyphenol-Functionalized Cubosomes as Thrombolytic Drug Carriers.
Controlling gene expression with deep generative design of regulatory DNA.

ACS Nano. 2022 Aug 29.

Engineering Lipid Nanoparticles for Enhanced Intracellular Delivery of mRNA through Inhalation.

Jeonghwan Kim, Antony Jozic, Yuxin Lin, Yulia Eygeris, Elissa Bloom, Xiaochen Tan, Christopher Acosta, Kelvin D MacDonald, Kevin D Welsher, Gaurav Sahay.

  Despite lipid nanoparticles' (LNPs) success in the effective and safe delivery of mRNA vaccines, an inhalation-based mRNA therapy for lung diseases remains challenging. LNPs tend to disintegrate due to shear stress during aerosolization, leading to ineffective delivery. Therefore, LNPs need to remain stable through the process of nebulization and mucus penetration, yet labile enough for endosomal escape. To meet these opposing needs, we utilized PEG lipid to enhance the surficial stability of LNPs with the inclusion of a cholesterol analog, β-sitosterol, to improve endosomal escape. Increased PEG concentrations in LNPs enhanced the shear resistance and mucus penetration, while β-sitosterol provided LNPs with a polyhedral shape, facilitating endosomal escape. The optimized LNPs exhibited a uniform particle distribution, a polyhedral morphology, and a rapid mucosal diffusion with enhanced gene transfection. Inhaled LNPs led to localized protein production in the mouse lung without pulmonary or systemic toxicity. Repeated administration of these LNPs led to sustained protein production in the lungs. Lastly, mRNA encoding the cystic fibrosis transmembrane conductance regulator (CFTR) was delivered after nebulization to a CFTR-deficient animal model, resulting in the pulmonary expression of this therapeutic protein. This study demonstrated the rational design approach for clinical translation of inhalable LNP-based mRNA therapies.

Keywords:  cystic fibrosis; inhalation; lung delivery; mRNA therapy; nebulization; pulmonary delivery; β-sitosterol

DOI:  https://doi.org/10.1021/acsnano.2c05647
Adv Drug Deliv Rev. 2022 Aug 27. pii: S0169-409X(22)00410-0. [Epub ahead of print] 114520

A proposed mathematical description of in vivo nanoparticle delivery.

Jamie L Y Wu, Benjamin P Stordy, Luan N M Nguyen, Christopher P Deutschman, Warren C W Chan.

  Nanoparticles are promising vehicles for the precise delivery of molecular therapies to diseased sites. Nanoparticles interact with a series of tissues and cells before they reach their target, which causes less than 1% of administered nanoparticles to be delivered to these target sites. Researchers have been studying the nano-bio interactions that mediate nanoparticle delivery to develop guidelines for designing nanoparticles with enhanced delivery properties. In this review article, we define these nano-bio interactions as a series of mathematical equations that quantitatively describe the nanoparticle delivery process. We employ a compartment model framework to describe delivery where nanoparticles are either (1) at the site of administration, (2) in the vicinity of target cells, (3) internalized by the target cells, or (4) sequestered away in off-target sites or eliminated from the body. This framework explains how different biological processes govern nanoparticle transport between these compartments, and the role of intercompartmental transport rates in determining the final nanoparticle delivery efficiency. Our framework provides guiding principles to engineer nanoparticles for improved targeted delivery.

Keywords:  Drug delivery; Nano-bio interactions; Nanoparticles; Targeting

DOI:  https://doi.org/10.1016/j.addr.2022.114520
Nano Lett. 2022 Aug 29.

Simulations of DNA-Origami Self-Assembly Reveal Design-Dependent Nucleation Barriers.

Alexander Cumberworth, Daan Frenkel, Aleks Reinhardt.

  Nucleation is the rate-determining step in the kinetics of many self-assembly processes. However, the importance of nucleation in the kinetics of DNA-origami self-assembly, which involves both the binding of staple strands and the folding of the scaffold strand, is unclear. Here, using Monte Carlo simulations of a lattice model of DNA origami, we find that some, but not all, designs can have a nucleation barrier and that this barrier disappears at lower temperatures, rationalizing the success of isothermal assembly. We show that the height of the nucleation barrier depends primarily on the coaxial stacking of staples that are adjacent on the same helix, a parameter that can be modified with staple design. Creating a nucleation barrier to DNA-origami assembly could be useful in optimizing assembly times and yields, while eliminating the barrier may allow for fast molecular sensors that can assemble/disassemble without hysteresis in response to changes in the environment.

Keywords:  DNA origami; coarse-grained models; control of nucleation; isothermal assembly; self-assembly

DOI:  https://doi.org/10.1021/acs.nanolett.2c01372
J Am Chem Soc. 2022 Aug 30.

Programmable Assembly of Amphiphilic DNA through Controlled Cholesterol Stacking.

Jin Liu, Liman Chen, Tingting Zhai, Wei Li, Yuehua Liu, Hongzhou Gu.

The excellent programmability and modifiability of DNA has enabled chemists to reproduce a series of specific molecular interactions in self-assembled synthetic systems. Among diverse modifications, cholesterol conjugation can turn DNA into an amphiphilic molecule (cholesterol-DNA), driving the formation of DNA assemblies through the cholesterol-endowed hydrophobic interaction. However, precise control of such an assembly process remains difficult because of the unbiased accumulation of cholesterol. Here, we report the serendipitous discovery of the favored tetramerization of cholesterol in cholesterol-DNA copolymers that carry the cholesterol modification at the blunt end of DNA. The discovery expands the repertoire of controllable molecular interactions by DNA and provides an effective way to precisely control the hydrophobic stacking of cholesterol for programmed cholesterol-DNA assembly.

DOI: https://doi.org/10.1021/jacs.2c06610
Nat Commun. 2022 Sep 01. 13(1): 5127

Bacteria loaded with glucose polymer and photosensitive ICG silicon-nanoparticles for glioblastoma photothermal immunotherapy.

Rong Sun, Mingzhu Liu, Jianping Lu, Binbin Chu, Yunmin Yang, Bin Song, Houyu Wang, Yao He.

Bacteria can bypass the blood-brain barrier (BBB), suggesting the possibility of employment of bacteria for combating central nervous system diseases. Herein, we develop a bacteria-based drug delivery system for glioblastoma (GBM) photothermal immunotherapy. The system, which we name as 'Trojan bacteria', consists of bacteria loaded with glucose polymer and photosensitive ICG silicon-nanoparticles. In an orthotopic GBM mouse model, we demonstrate that the intravenously injected bacteria bypass the BBB, targeting and penetrating GBM tissues. Upon 808 nm-laser irradiation, the photothermal effects produced by ICG allow the destruction of bacterial cells and the adjacent tumour cells. Furthermore, the bacterial debris as well as the tumour-associated antigens promote antitumor immune responses that prolong the survival of GBM-bearing mice. Moreover, we demonstrate the residual bacteria are effectively eliminated from the body, supporting the potential therapeutic use of this system.

DOI: https://doi.org/10.1038/s41467-022-32837-5
Adv Sci (Weinh). 2022 Aug 30. e2202829

Abalone-Inspired Adhesive and Photo-Responsive Microparticle Delivery Systems for Periodontal Drug Therapy.

Chuanhui Song, Danqing Huang, Cheng Zhao, Yuanjin Zhao.

  Antibiotics provide promising strategies for treating periodontitis, while their delivery and controllable release with desired oral retention remain challenging. Here, inspired by the unique suction-cup structures of abalones, a novel adhesive and photo-responsive microparticle (MP) delivery system is developed to treat periodontitis through microfluidic electrospray technology. Such MPs are generated by quickly ionic cross-linking of sodium alginate together with photo-curing of poly(ethylene glycol) diacrylate of the distorted microfluidic droplets during their high-speed dropping into calcium chloride solution. Attributing to their unique concave structures, the abalone-inspired MPs exhibit desired underwater adhesion ability and stability under running water. In addition, due to the loading of antibiotics minocycline hydrochloride and near-infrared (NIR)-responsive black phosphorus during their fabrication, the resultant MPs can not only eradicate bacteria directly, but also realize a controllable and effective drug release upon NIR irradiation. Based on these features, it is demonstrated from in vivo periodontitis that the abalone-inspired MPs are firmly adhesive and can controlled-release drugs on the tooth, and thus have outstanding antibacterial efficacy against Porphyromonas gingivalis. These results indicate the particular values of the abalone-inspired MPs for oral-related disease treatment.

Keywords:  antibacterial microparticles; bioinspired materials; drug deliveries; microfluidics; particles; periodontitis

DOI:  https://doi.org/10.1002/advs.202202829
Nano Lett. 2022 Aug 29.

Enhanced Intracellular Transcytosis of Nanoparticles by Degrading Extracellular Matrix for Deep Tissue Radiotherapy of Pancreatic Adenocarcinoma.

Li Wang, Jiaxiang Dou, Wei Jiang, Qin Wang, Yi Liu, Hang Liu, Yucai Wang.

  Intracellular transcytosis can enhance the penetration of nanomedicines to deep avascular tumor tissues, but strategies that can improve transcytosis are limited. In this study, we discovered that pyknomorphic extracellular matrix (ECM) is a shield that impairs endocytosis of nanoparticles and their movement between adjacent cells and thus limits their active transcytosis in tumors. We further showed that degradation of pivotal constituent of ECM (i.e., collagen) effectively enhances intracellular transcytosis of nanoparticles. Specifically, a collagenase conjugating transcytosis nanoparticle (Col-TNP) can dissociate into collagenase and cationized gold nanoparticles in response to tumor acidity, which enables their ECM tampering ability and active transcytosis in tumors. The breakage of ECM further enhances the active transcytosis of cationized nanoparticles into deep tumor tissues as well as radiosensitization efficacy of pancreatic adenocarcinoma. Our study opens up new paths to enhance the active transcytosis of nanomedicines for the treatment of cancers and other diseases.

Keywords:  Cancer Radiotherapy; Extracellular Matrix; Pancreatic Adenocarcinoma; Programmed Self-assembly; Transcytosis

DOI:  https://doi.org/10.1021/acs.nanolett.2c01005
Adv Healthc Mater. 2022 Aug 29. e2201151

Polyphenol-Functionalized Cubosomes as Thrombolytic Drug Carriers.

Haitao Yu, Jason S Palazzolo, Yi Ju, Be'eri Niego, Shuaijun Pan, Christoph E Hagemeyer, Frank Caruso.

  The safe administration of thrombolytic agents is a challenge for the treatment of acute thrombosis. Lipid-based nanoparticle drug delivery technologies present opportunities to overcome the existing clinical limitations and deliver thrombolytic therapy with enhanced therapeutic outcomes and safety. Herein, lipid cubosomes as nanocarriers are used for encapsulating thrombolytic drugs is examined. The lipid cubosomes are coated with a low-fouling peptide that is incorporated within a metal-phenolic network (MPN) and which encapsulate the thrombolytic drug urokinase-type plasminogen activator (uPA). The peptide-containing MPN (pep-MPN) coating inhibits the direct contact of uPA with the surrounding environment, as assessed by an in vitro plasminogen activation assay and an ex vivo whole blood clot degradation assay. The pep-MPN-coated cubosomes prepared with 22 wt% peptide demonstrate a cell membrane-dependent thrombolytic activity, which is attributed to their fusogenic lipid behavior. Moreover, compared with the uncoated lipid cubosomes, the uPA-loaded pep-MPN-coated cubosomes demonstrate significantly reduced nonspecific cell association (<10% of the uncoated cubosomes) in the whole blood assay, prolonged circulating half-life, and reduced splenic uPA accumulation in mice. These studies confirm the preserved bioactivity and cell membrane-dependent release of uPA within pep-MPN-coated lipid cubosomes, highlighting their potential as a delivery vehicle for thrombolytic drugs. This article is protected by copyright. All rights reserved.

Keywords:  lipid cubosomes; metal-polyphenol networks; plasminogen activators; thrombolytic nanoparticles; urokinase

DOI:  https://doi.org/10.1002/adhm.202201151
Nat Commun. 2022 Aug 30. 13(1): 5099

Controlling gene expression with deep generative design of regulatory DNA.

Jan Zrimec, Xiaozhi Fu, Azam Sheikh Muhammad, Christos Skrekas, Vykintas Jauniskis, Nora K Speicher, Christoph S Börlin, Vilhelm Verendel, Morteza Haghir Chehreghani, Devdatt Dubhashi, Verena Siewers, Florian David, Jens Nielsen, Aleksej Zelezniak.

Design of de novo synthetic regulatory DNA is a promising avenue to control gene expression in biotechnology and medicine. Using mutagenesis typically requires screening sizable random DNA libraries, which limits the designs to span merely a short section of the promoter and restricts their control of gene expression. Here, we prototype a deep learning strategy based on generative adversarial networks (GAN) by learning directly from genomic and transcriptomic data. Our ExpressionGAN can traverse the entire regulatory sequence-expression landscape in a gene-specific manner, generating regulatory DNA with prespecified target mRNA levels spanning the whole gene regulatory structure including coding and adjacent non-coding regions. Despite high sequence divergence from natural DNA, in vivo measurements show that 57% of the highly-expressed synthetic sequences surpass the expression levels of highly-expressed natural controls. This demonstrates the applicability and relevance of deep generative design to expand our knowledge and control of gene expression regulation in any desired organism, condition or tissue.

DOI: https://doi.org/10.1038/s41467-022-32818-8