bims-drudre Biomed News
on Targeted drug delivery and programmed release mechanisms
Issue of 2022‒10‒30
eight papers selected by
Ceren Kimna
Technical University of Munich
  1. Cell-specific bioorthogonal tagging of glycoproteins.
  2. Penetrating Macrophage-Based Nanoformulation for Periodontitis Treatment.
  3. Membrane-Specific Binding of 4 nm Lipid Nanoparticles Mediated by an Entropy-Driven Interaction Mechanism.
  4. Expression of mosquito miRNAs in entomopathogenic fungus induces pathogen-mediated host RNA interference and increases fungal efficacy.
  5. Delivery of RNAs to Specific Organs by Lipid Nanoparticles for Gene Therapy.
  6. Mechanoactive Nanocomposite Hydrogel to Accelerate Wound Repair in Movable Parts.
  7. Deviations in MicroRNA-21 Expression Patterns Identify a Therapeutic Target for Diabetic Wound Healing.
  8. A Programmable, DNA-Exclusively-Guided Argonaute DNase and Its Higher Cleavage Specificity Achieved by 5'-Hydroxylated Guide.
  1. Nat Commun. 2022 Oct 25. 13(1): 6237
    Cell-specific bioorthogonal tagging of glycoproteins.
    Anna Cioce, Beatriz Calle, Tatiana Rizou, Sarah C Lowery, Victoria L Bridgeman, Keira E Mahoney, Andrea Marchesi, Ganka Bineva-Todd, Helen Flynn, Zhen Li, Omur Y Tastan, Chloe Roustan, Pablo Soro-Barrio, Mahmoud-Reza Rafiee, Acely Garza-Garcia, Aristotelis Antonopoulos, Thomas M Wood, Tessa Keenan, Peter Both, Kun Huang, Fabio Parmeggian, Ambrosius P Snijders, Mark Skehel, Svend Kjær, Martin A Fascione, Carolyn R Bertozzi, Stuart M Haslam, Sabine L Flitsch, Stacy A Malaker, Ilaria Malanchi, Benjamin Schumann.
      Altered glycoprotein expression is an undisputed corollary of cancer development. Understanding these alterations is paramount but hampered by limitations underlying cellular model systems. For instance, the intricate interactions between tumour and host cannot be adequately recapitulated in monoculture of tumour-derived cell lines. More complex co-culture models usually rely on sorting procedures for proteome analyses and rarely capture the details of protein glycosylation. Here, we report a strategy termed Bio-Orthogonal Cell line-specific Tagging of Glycoproteins (BOCTAG). Cells are equipped by transfection with an artificial biosynthetic pathway that transforms bioorthogonally tagged sugars into the corresponding nucleotide-sugars. Only transfected cells incorporate bioorthogonal tags into glycoproteins in the presence of non-transfected cells. We employ BOCTAG as an imaging technique and to annotate cell-specific glycosylation sites in mass spectrometry-glycoproteomics. We demonstrate application in co-culture and mouse models, allowing for profiling of the glycoproteome as an important modulator of cellular function.
    DOI:  https://doi.org/10.1038/s41467-022-33854-0
  2. ACS Nano. 2022 Oct 26.
    Penetrating Macrophage-Based Nanoformulation for Periodontitis Treatment.
    Na Yan, Junchao Xu, Guolin Liu, Chao Ma, Lin Bao, Yalin Cong, Ziyao Wang, Yuliang Zhao, Weihua Xu, Chunying Chen.
      Periodontitis is a chronic inflammatory disease caused by the interaction of oral microorganisms with the host immune response. Porphyromonas gingivalis (P.g.) acts as a key mediator in subverting the homeostasis of the local immune system. On the one hand, P.g. inhibits phagocytosis and the killing capacity of immune cells. On the other hand, P.g. increases selective cytokine release, which is beneficial to its further proliferation. Here, we prepared a penetrating macrophage-based nanoformulation (MZ@PNM)-encapsulating hydrogel (MZ@PNM@GCP) that responded to the periodontitis microenvironment. MZ@PNM targeted P.g. via the Toll-like receptor complex 2/1 (TLR2/1) on its macrophage-mimicking membrane, then directly killed P.g. through disruption of bacterial structural integrity by the cationic nanoparticles and intracellular release of an antibacterial drug, metronidazole (MZ). Meanwhile, MZ@PNM interrupted the specific binding of P.g. to immune cells and neutralized complement component 5a (C5a), preventing P.g. subversion of periodontal host immune response. Overall, MZ@PNM@GCP showed potent efficacy in periodontitis treatment, restoring local immune function and killing pathogenic bacteria, while exhibiting favorable biocompatibility, all of which have been demonstrated both in vivo and in vitro.
    Keywords:  Porphyromonas gingivalis; host immune dysfunction; membrane cloaking nanoparticle; periodontitis treatment; responsive hydrogel
    DOI:  https://doi.org/10.1021/acsnano.2c05923
  3. ACS Nano. 2022 Oct 24.
    Membrane-Specific Binding of 4 nm Lipid Nanoparticles Mediated by an Entropy-Driven Interaction Mechanism.
    Luping Ou, Haibo Chen, Bing Yuan, Kai Yang.
      Lipid nanoparticles (LNPs) are a leading biomimetic drug delivery platform due to their distinctive advantages and highly tunable formulations. A mechanistic understanding of the interaction between LNPs and cell membranes is essential for developing the cell-targeted carriers for precision medicine. Here the interactions between sub 10 nm cationic LNPs (cLNPs; e.g., 4 nm in size) and varying model cell membranes are systematically investigated using molecular dynamics simulations. We find that the membrane-binding behavior of cLNPs is governed by a two-step mechanism that is initiated by direct contact followed by a more crucial lipid exchange (dissociation of cLNP's coating lipids and subsequent flip and intercalation into the membrane). Importantly, our simulations demonstrate that the membrane binding of cLNPs is an entropy-driven process, which thus enables cLNPs to differentiate between membranes having different lipid compositions (e.g., the outer and inner membranes of bacteria vs the red blood cell membranes). Accordingly, the possible strategies to drive the membrane-targeting behaviors of cLNPs, which mainly depend on the entropy change in the complicated entropy-enthalpy competition of the cLNP-membrane interaction process, are investigated. Our work unveils the molecular mechanism underlying the membrane selectivity of cLNPs and provides useful hints to develop cLNPs as membrane-targeting agents for precision medicine.
    Keywords:  entropy-driven process; lipid nanoparticles; membrane-specific binding; molecular dynamics simulations; targeted delivery
    DOI:  https://doi.org/10.1021/acsnano.2c04774
  4. Cell Rep. 2022 Oct 25. pii: S2211-1247(22)01383-3. [Epub ahead of print]41(4): 111527
    Expression of mosquito miRNAs in entomopathogenic fungus induces pathogen-mediated host RNA interference and increases fungal efficacy.
    Chunlai Cui, Yan Wang, Yifei Li, Peilu Sun, Jinyong Jiang, Hongning Zhou, Jingnan Liu, Sibao Wang.
      The growing threat of insecticide resistance prompts the urgent need to develop additional tools for mosquito control. Entomopathogenic fungi provide an eco-friendly alternative to chemical insecticides. One limitation to the use of mycoinsecticides is their relatively low virulence. Here, we report an approach for suppressing mosquito immunity and increasing fungal virulence. We engineered Beauveria bassiana to express Aedes immunosuppressive microRNAs (miRNAs) to induce host RNA interference (RNAi) immune responses. We show that engineered strains can produce and deliver the miRNAs into host cells to activate cross-kingdom RNAi during infection and suppress mosquito immunity by targeting multiple host genes, thereby dramatically increasing fungal virulence against Aedes aegypti and Galleria mellonella larvae. Importantly, expressing host miRNAs also significantly increases fungal virulence against insecticide-resistant mosquitoes, creating potential for insecticide-resistance management. This pathogen-mediated RNAi (pmRNAi)-based approach provides an innovative strategy to enhance the efficacy of fungal insecticides and eliminate the likelihood of resistance development.
    Keywords:  Aedes aegypti; CP: Microbiology; cross-kingdom RNAi; fungal entomopathogen; fungal insecticides; fungal pathogenicity; fungal virulence; insect immunity; insecticide resistance; microRNA; mosquitoes
    DOI:  https://doi.org/10.1016/j.celrep.2022.111527
  5. Pharmaceutics. 2022 Oct 07. pii: 2129. [Epub ahead of print]14(10):
    Delivery of RNAs to Specific Organs by Lipid Nanoparticles for Gene Therapy.
    Kelly Godbout, Jacques P Tremblay.
      Gene therapy holds great promise in the treatment of genetic diseases. It is now possible to make DNA modifications using the CRISPR system. However, a major problem remains: the delivery of these CRISPR-derived technologies to specific organs. Lipid nanoparticles (LNPs) have emerged as a very promising delivery method. However, when delivering LNPs intravenously, most of the cargo is trapped by the liver. Alternatively, injecting them directly into organs, such as the brain, requires more invasive procedures. Therefore, developing more specific LNPs is crucial for their future clinical use. Modifying the composition of the lipids in the LNPs allows more specific deliveries of the LNPs to some organs. In this review, we have identified the most effective compositions and proportions of lipids for LNPs to target specific organs, such as the brain, lungs, muscles, heart, liver, spleen, and bones.
    Keywords:  CRISPR/Cas9 delivery; gene therapy; lipid nanoparticles; mRNA delivery; specific organ delivery
    DOI:  https://doi.org/10.3390/pharmaceutics14102129
  6. ACS Nano. 2022 Oct 27.
    Mechanoactive Nanocomposite Hydrogel to Accelerate Wound Repair in Movable Parts.
    Chao Cai, Huimin Zhu, Yujie Chen, Yutong Guo, Zhi Yang, Hua Li, Hezhou Liu.
      Dynamic full-thickness skin wound healing remains an intricate problem due to the humid environment and frequent exercise. Recently, multifunctional hydrogels have a great promise in wound repair. However, traditional hydrogels only keep the wound moist, protect the wound from bacterial infection, and cannot actively drive dynamic wound closure. Inspired by embryo wound active closure, we constructed a double-sided thermoresponsive mechanoactive (DTM) hydrogel that combines good flexibility, self-healing, wet-tissue adhesion, and antibacterial functions. The strong adhesion of the hydrogel to biological tissues is attributed to "multiple hydrogen bonding clusters" without any chemical reaction. The contraction force triggered by temperature is quickly transmitted to dynamic wound edges to resist external mechanical forces and drive wound closure, which can effectively avoid damage to surrounding healthy tissue and reduce the risk of scarring, infection, and inflammation caused by sutures, staples, or clips. Strikingly, in vivo, this hydrogel bandage actively enhanced wound repair in a full-thickness skin defect model by promoting collagen deposition, facilitating angiogenesis, and accelerating wound re-epithelialization. This mechanoactive biological method will provide a facile strategy for joint wound management and demonstrates strong potential in tissue remodeling.
    Keywords:  double-sided; dynamic wound; hydrogel; mechanoactive; thermoresponsive
    DOI:  https://doi.org/10.1021/acsnano.2c07483
  7. J Immunobiol. 2021 ;pii: 155. [Epub ahead of print]6(1):
    Deviations in MicroRNA-21 Expression Patterns Identify a Therapeutic Target for Diabetic Wound Healing.
    Shaquia Idlett-Ali, Kenneth W Liechty, Junwang Xu.
      Chronic inflammation plays a major role in impaired healing of diabetic wounds. Mounting evidence highlights the role of controlled, sequential polarization of macrophages in producing the appropriate progression through the stages of wound healing: inflammation (pro- inflammatory stage), proliferation and remodeling (regenerative stage). Non-coding RNAs, including microRNAs, maintain critical roles in regulating normal biological processes, such as wound healing; and are being explored as therapeutic targets for modulating dysfunction in disease states. Interestingly, microRNA-21 (miR-21) has a suggested role in the induction of pro-inflammatory and regenerative stages of healing, but clarity remains elusive on the specific mechanisms determining the direction miR-21 shifts wound healing processes. Findings by Liechty et al. in International Journal of Molecular Science indicate an important role of miR-21, in shaping the wound healing cascade by preferentially inducing M1-like (pro-inflammatory) polarization of macrophages in the early phase of diabetic wound healing. Persistent elevation of miR-21 is suggestive of sustained pro-inflammatory drive, and subsequent wound healing impairment, in the skin of diabetic murine models and diabetic human skin. Differences in the expression patterns of miR-21 during diabetic wound healing identifies the potentially critical role of therapeutic timing, for miR-21 based therapies, in driving positive outcomes for patients.
    Keywords:  Diabetes; Hyperglycemia; Inflammation; Wound healing; miR-21
  8. Biomolecules. 2022 Sep 21. pii: 1340. [Epub ahead of print]12(10):
    A Programmable, DNA-Exclusively-Guided Argonaute DNase and Its Higher Cleavage Specificity Achieved by 5'-Hydroxylated Guide.
    Shichao Sun, Dejin Xu, Lin Zhu, Bei Hu, Zhen Huang.
      Argonaute proteins exist widely in eukaryotes and prokaryotes, and they are of great potential for molecular cloning, nucleic acid detection, DNA assembly, and gene editing. However, their overall properties are not satisfactory and hinder their broad applications. Herein, we investigated a prokaryotic Argonaute nuclease from a mesophilic bacterium Clostridium disporicum (CdAgo) and explored its overall properties, especially with 5'-hydroxylated (5'-OH) guides. We found that CdAgo can exclusively use single-stranded DNA (ssDNA) as guide to cleave ssDNA and plasmid targets. Further, we found the length of the efficient guide is narrower for the 5'-OH guide (17-20 nt) than for the 5'-phosphorylated guide (5'-P, 14-21 nt). Furthermore, we discovered that the 5'-OH guides can generally offer stronger mismatch discrimination than the 5'-P ones. The 5'-OH guides offer the narrower length range, higher mismatch discrimination and more accurate cleavage than the 5'-P guides. Therefore, 5'-OH-guide-directed CdAgo has great potential in biological and biomedical applications.
    Keywords:  Argonaute; Clostridium disporicum; DNase; mesophilic bacterium; specificity
    DOI:  https://doi.org/10.3390/biom12101340
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