bims-drudre Biomed News
on Targeted drug delivery and programmed release mechanisms
Issue of 2021‒10‒31
twelve papers selected by
Ceren Kimna
Technical University of Munich

  1. Angew Chem Int Ed Engl. 2021 Oct 29.
      Framework nucleic acids (FNAs) represent nanoscale oligonucleotide assemblies with unique physical, chemical, and biological properties different from their building blocks. Following simple Watson-Crick base-pairing rules, arbitrary DNA frameworks with diverse shapes, sizes, and dimensions can be prepared with high reproducibility and stability. The programmable assembly of nucleic acids into FNAs presents a highly controllable model for nano-bio interaction studies and allows for scrutiny of "nanostructure-activity relationships." Herein, we present an overview of the recent progress of FNAs in the hope of deepening our understanding of nano-bio interfacing. By investigating various FNAs, we summarize their biological profiles and immune responses as functions of their shape, sizes, and surface charges. We then highlight recent efforts of applying FNAs for biomedical applications and discuss the challenges of FNAs for potential clinical translation. We believe that this mini-review can bring up-to-date information on FNA and shed light on how their design may be harnessed for selective biomedical applications.
    Keywords:  DNA nanotechnology; Framework nucleic acid (FNA); nano-bio interaction; nuclear imaging; nuclear medicine
  2. Adv Mater. 2021 Oct 25. e2106865
      Embolization is a catheter-based minimally invasive procedure that deliberately occludes diseased blood vessels for treatment purposes. We report a novel silk based embolic material (SEM) that was developed and optimized to provide tandem integration of both embolization and the delivery of therapeutics. Natural silk was processed into fibroin proteins of varying lengths and combined with charged nanoclay particles to allow visibility and injectability using clinical catheters as small as 600 microns in diameter at lengths >100 cm. SEMs loaded with fluorochrome labeled bovine albumin and Nivolumab, which is among the most used immunotherapy drugs world-wide, demonstrated a sustained release profile in vitro over 28 days. In a porcine renal survival model, SEMs with labeled albumin and Nivolumab successfully embolized porcine arteries without recanalization and led to the delivery of both albumin and Nivolumab into the interstitial space of the renal cortex. Mechanistically, we show that tissue delivery is most optimal when the internal elastic membrane of the embolized artery is disrupted. SEM is a potential next-generation multifunctional embolic agent that can achieve embolization and deliver a wide range of therapeutics to treat vascular diseases including tumors. This article is protected by copyright. All rights reserved.
    Keywords:  embolization; immunotherapy; nanoclay; silk; vascular interventions
  3. Angew Chem Int Ed Engl. 2021 Oct 25.
      Effective endosomal escape after cellular uptake represents a major challenge in the field of nanodelivery, as the majority of drug payloads must localize to subcellular compartments other than the endosomes in order to exert activity. In nature, viruses can readily deliver their genetic material to the cytosol of host cells by triggering membrane fusion after endocytosis. For the influenza A virus, the hemagglutinin (HA) protein found on its surface fuses the viral envelope with surrounding membrane at endosomal pH values. Here, biomimetic nanoparticles capable of endosomal escape were fabricated using a membrane coating derived from cells engineered to express HA on their surface. When evaluated in vitro, these virus-mimicking nanoparticles were able to deliver an mRNA payload to the cytosolic compartment of target cells, resulting in the successful expression of the encoded protein. When the mRNA-loaded nanoparticles were administered in vivo, protein expression levels were significantly increased in both local and systemic delivery scenarios. We therefore conclude that utilizing genetic engineering approaches to express viral fusion proteins on the surface of cell membrane-coated nanoparticles is a viable strategy for modulating the intracellular localization of encapsulated cargoes.
    Keywords:  cell membrane coating; endosomal escape; genetic engineering; hemagglutinin; mRNA
  4. Nanoscale Horiz. 2021 Oct 25. 6(11): 907-912
      In this design, small CuS nanoparticles (NPs) were intracellularly self-assembled into large supramolecular aggregates via host-guest interactions between sequentially internalized β-cyclodextrin-capped CuS NPs and ferrocene-capped CuS NPs inside macrophages, thus the efflux of CuS NPs was significantly inhibited during the macrophage-hitchhiking delivery. Biodistribution studies in mice confirmed the dramatically enhanced deposition of CuS NPs in the tumor tissue of mice injected with macrophages carrying intracellular CuS aggregates, in comparison to that of mice treated with macrophages carrying CuS NPs. In response to the inflammatory tumor microenvironment, the oxidation of ferrocene would dissociate the β-cyclodextrin-ferrocene host-guest pair, driving disassembly of the CuS aggregates and release of small CuS NPs for deep tissue penetration and enhanced photothermal therapy. This precisely controlled intracellular self-assembly and disassembly of the nanomedicine inside macrophages provides a novel cell-hitchhiking delivery strategy that not only minimizes premature leakage of the nanomedicine but also greatly improves the delivery efficiency and tumor penetration for safe, effective tumor therapy.
  5. Nat Nanotechnol. 2021 Oct 25.
      Trivalent arsenic (AsIII) is an effective agent for treating patients with acute promyelocytic leukaemia, but its ionic nature leads to several major limitations like low effective concentrations in leukaemia cells and substantial off-target cytotoxicity, which limits its general application to other types of leukaemia. Here, building from our clinical discovery that cancerous cells from patients with different leukaemia forms featured stable and strong expression of CD71, we designed a ferritin-based As nanomedicine, As@Fn, that bound to leukaemia cells with very high affinity, and efficiently delivered cytotoxic AsIII into a large diversity of leukaemia cell lines and patient cells. Moreover, As@Fn exerted strong anti-leukaemia effects in diverse cell-line-derived xenograft models, as well as in a patient-derived xenograft model, in which it consistently outperformed the gold standard, showing its potential as a precision treatment for a variety of leukaemias.
  6. Nat Biotechnol. 2021 Oct 28.
      The ability to control translation of endogenous or exogenous RNAs in eukaryotic cells would facilitate a variety of biotechnological applications. Current strategies are limited by low fold changes in transgene output and the size of trigger RNAs (trRNAs). Here we introduce eukaryotic toehold switches (eToeholds) as modular riboregulators. eToeholds contain internal ribosome entry site sequences and form inhibitory loops in the absence of a specific trRNA. When the trRNA is present, eToeholds anneal to it, disrupting the inhibitory loops and allowing translation. Through optimization of RNA annealing, we achieved up to 16-fold induction of transgene expression in mammalian cells. We demonstrate that eToeholds can discriminate among viral infection status, presence or absence of gene expression and cell types based on the presence of exogenous or endogenous RNA transcripts.
  7. Adv Sci (Weinh). 2021 Oct 27. e2101840
      The absence of tumor antigens leads to a low response rate, which represents a major challenge in immune checkpoint blockade (ICB) therapy. Pyroptosis, which releases tumor antigens and damage-associated molecular patterns (DAMPs) that induce antitumor immunity and boost ICB efficiency, potentially leads to injury when occurring in normal tissues. Therefore, a strategy and highly efficient agent to induce tumor-specific pyroptosis but reduce pyroptosis in normal tissues is urgently required. Here, a smart tumor microenvironmental reactive oxygen species (ROS)/glutathione (GSH) dual-responsive nano-prodrug (denoted as MCPP) with high paclitaxel (PTX) and photosensitizer purpurin 18 (P18) loading is rationally designed. The ROS/GSH dual-responsive system facilitates the nano-prodrug response to high ROS/GSH in the tumor microenvironment and achieves optimal drug release in tumors. ROS generated by P18 after laser irradiation achieves controlled release and induces tumor cell pyroptosis with PTX by chemo-photodynamic therapy. Pyroptotic tumor cells release DAMPs, thus initiating adaptive immunity, boosting ICB efficiency, achieving tumor regression, generating immunological memory, and preventing tumor recurrence. Mechanistically, chemo-photodynamic therapy and control-release PTX synergistically induce gasdermin E (GSDME)-related pyroptosis. It is speculated that inspired chemo-photodynamic therapy using the presented nano-prodrug strategy can be a smart strategy to trigger pyroptosis and augment ICB efficiency.
    Keywords:  immunotherapy; paclitaxel; prodru gs; pyroptosis; tumor microenvironment
  8. Adv Mater. 2021 Oct 25. e2105976
      Photothermal therapy holds great promise for cancer treatment due to its effective tumor ablation and minimal invasiveness. We report herein a new class of biodegradable photothermal agents with effective adsorption in both Near-Infrared-I and II windows for deep tumor therapy. As demonstrated in a deep-seated ovarian cancer model, photothermal therapy using 1064 nm irradiation effectively inhibits tumor progression and prolongs survival spans. This work provides a new design of photothermal agents towards a more effective therapy of tumors. This article is protected by copyright. All rights reserved.
    Keywords:  NIR-II; biodegradability; deep penetration; photothermal agents; photothermal therapy
  9. Small. 2021 Oct 29. e2104359
      MicroRNAs (miRs) play an important role in regulating gene expression. Limited by their instabilities, miR therapeutics require delivery vehicles. Tetrahedral framework nucleic acids (tFNAs) are potentially applicable to drug delivery because they prominently penetrate tissue and are taken up by cells. However, tFNA-based miR delivery strategies have failed to separate the miRs after they enter cells, affecting miR efficiency. In this study, an RNase H-responsive sequence is applied to connect a sticky-end tFNA (stFNA) and miR-2861, which is a model miR, to target the expression of histone deacetylase 5 (HDAC5) in bone marrow mesenchymal stem cells. The resultant bioswitchable nanocomposite (stFNA-miR) enables efficient miR-2861 unloading and deployment after intracellular delivery, thereby inhibiting the expression of HDAC5 and promoting osteogenic differentiation. stFNA-miR also facilitated ideal bone repair via topical injection. In conclusion, a versatile miR delivery strategy is offered for various biomedical applications that necessitate modulation of gene expression.
    Keywords:  DNA nanotechnology; bone regeneration; drug delivery; framework nucleic acid; microRNA
  10. Adv Mater. 2021 Oct 26. e2107177
      There has been considerable interest in developing synthetic micromotors with biofunctional, versatile, and adaptive capabilities for biomedical applications. In this perspective, cell membrane-functionalized micromotors emerge as an attractive platform. This new class of micromotors demonstrates enhanced propulsion and compelling performance in complex biological environments, making them suitable for various in vivo applications, including drug delivery, detoxification, immune modulation, and phototherapy. This article reviews various proof-of-concept studies based on different micromotor designs and cell membrane coatings in these areas. The review focuses on the motor structure and performance relationship and highlights how cell membrane functionalization overcomes the obstacles faced by traditional synthetic micromotors while imparting them with unique capabilities. Overall, the cell membrane-functionalized micromotors are expected to advance micromotor research and facilitate its translation towards practical uses. This article is protected by copyright. All rights reserved.
    Keywords:  cell membrane; detoxification; drug delivery; immunotherapy; micromotor; phototherapy
  11. ACS Nano. 2021 Oct 26.
      Accurate diagnosis and precise and effective treatment are currently the two magic weapons for dealing with cancer. However, a single marker is often associated with multiple cellular events, which is not conducive to accurate diagnosis, and overly mild treatment methods often make the treatment effect unsatisfactory. In this paper, we construct a Au/Pd octopus nanoparticle-DNA nanomachine (Au/Pd ONP-DNA nanomachine) as a fully automatic diagnosis and treatment logic system. In this system, multiple DNA components are targeting detection units, Au/Pd ONPs act as carriers, and Au/Pd ONPs with an 808 nm laser is the treatment unit. In order to achieve the purpose of precise treatment, we will detect two secondary markers under the premise of detecting one major tumor marker. When all of the designated targets are detected (the logic system input is (1, 1, 1), and the output is (1, 1)), the 808 nm laser can be programmed to automatically radiate tumors and perform photothermal therapy and photodynamic therapy. In vivo and in vitro experiments show that this logic system not only can accurately identify tumor cells but also has considerable therapeutic effects.
    Keywords:  automatic response; cancer; logic circuit; miRNA; multimarker detection; oncotherapy
  12. Adv Mater. 2021 Oct 30. e2107315
      Iontophoresis is an electrical current-based, non-invasive drug delivery technology, which is particularly suitable for intraocular drug delivery. Current ocular iontophoresis devices use low current intensities that significantly limit macromolecule and nanoparticle (NP) delivery efficiency. Increasing current intensity leads to ocular tissue damage due to Joule heating and electrochemical (EC) reactions. Here, we describe a hydrogel ionic circuit (HIC)-based iontophoresis device for high-efficiency intraocular macromolecule and NP delivery. Our HIC-based device is capable of minimizing Joule heating, effectively buffering EC reaction-generated pH changes, and absorbing electrode overpotential-induced heating. As a result, our device allows safe application of high current intensities (∼87 mA cm-2 , more than 10 times higher than current ocular iontophoresis devices) to the eye with minimal ocular cell death and tissue damage. Our high-intensity iontophoresis significantly enhances intraocular macromolecule and NP delivery to both anterior and posterior segments by up to 300 times compared to conventional iontophoresis. Therapeutically effective concentrations of bevacizumab and dexamethasone are delivered to target tissue compartments within 10-20 min of iontophoresis application. Our studies highlight the significant safety enhancement enabled by a HIC-based device design and the potential of our device to deliver therapeutic doses of macromolecule and NP ophthalmic drugs within a clinically relevant time frame. This article is protected by copyright. All rights reserved.
    Keywords:  Aqueous two-phase systems; Hydrogel electrode; Ionic circuit; Iontophoresis; Ocular drug delivery