bims-drudre Biomed News
on Targeted drug delivery and programmed release mechanisms
Issue of 2022‒07‒24
seventeen papers selected by
Ceren Kimna
Technical University of Munich

  1. Nat Commun. 2022 Jul 21. 13(1): 4214
      Glioblastoma multiforme (GBM) is an aggressive brain cancer with a poor prognosis and few treatment options. Here, building on the observation of elevated lactate (LA) in resected GBM, we develop biomimetic therapeutic nanoparticles (NPs) that deliver agents for LA metabolism-based synergistic therapy. Because our self-assembling NPs are encapsulated in membranes derived from glioma cells, they readily penetrate the blood-brain barrier and target GBM through homotypic recognition. After reaching the tumors, lactate oxidase in the NPs converts LA into pyruvic acid (PA) and hydrogen peroxide (H2O2). The PA inhibits cancer cell growth by blocking histones expression and inducing cell-cycle arrest. In parallel, the H2O2 reacts with the delivered bis[2,4,5-trichloro-6-(pentyloxycarbonyl)phenyl] oxalate to release energy, which is used by the co-delivered photosensitizer chlorin e6 for the generation of cytotoxic singlet oxygen to kill glioma cells. Such a synergism ensures strong therapeutic effects against both glioma cell-line derived and patient-derived xenograft models.
  2. ACS Nano. 2022 Jul 18.
      Maximizing the tissue-targeting efficiency of nanomaterials while also protecting them from rapid clearance from the bloodstream and limiting their immunogenicity remains a central problem in the field of systemic-administered nanomedicine. Herein, we introduce a generalizable strategy to simultaneously increase tumor accumulation, prolong blood circulation, and limit nonspecific immune activation of nanomaterials via peptide-based, tumor-responsive, "sheddable" coatings. Spherical nucleic acids (SNAs) were designed and synthesized to contain an exterior coating composed of zwitterionic polypeptides with recognition sequences for tumor-associated proteases. In the presence of matrix metalloproteinases (MMPs), the polypetide coating is rapidly cleaved, leading to increased cellular uptake of these SNAs, relative to SNAs containing nonsheddable shells. Moreover, the zwitterionic nature of the polypeptide shell shields the SNAs from immune system recognition, which extends their blood circulation time and improves tumor accumulation and in vivo cellular uptake relative to control SNAs with no protective coating. Taken together, these results indicate that this strategy is a viable method for increasing nanoparticle tumor accumulation and can have utility for the systemic delivery of oligonucleotides and nanomaterials to target cells in vivo with low immunogenicity.
    Keywords:  PEGylation; immunogenicity; matrix metalloproteinase-cleavable; spherical nucleic acids; tumor accumulation; zwitterionic peptides
  3. Anal Chem. 2022 Jul 20.
      The high programmability of DNA molecules makes them particularly suitable for constructing artificial molecular machines to perform sophisticated functions by simulating complex living systems. However, intelligent DNA nanomachines which can perform precise tasks logically in complex environments still remain challenging. Herein, we develop a general strategy to design a pH-responsive programmable DNA (PRPD) nanomachine to perform multilayer DNA cascades, enabling precise sensing and calculation of intracellular biomolecules. The PRPD nanomachine is built on a four-stranded DNAzyme walker precursor with a DNA switch on the surface of an Au nanoparticle, which is capable of precisely responding to pH variations in living cells by sequence tuning. This multilayer DNA cascade networks have been applicated in spatially controlled imaging of intracellular microRNA, which efficiently avoided the DNA nanomachine activated by nonspecific extracellular molecules and achieved apparent signal amplification. Our strategy enables the sensing-computing-output functional integration of DNA nanomachines, facilitating the application of programmable and complex nanomachines in nanoengineering, chemistry, and biomedicine.
  4. ACS Appl Mater Interfaces. 2022 Jul 22.
      DNA nanostructure-based responsive drug delivery has become an increasingly potent method in cancer therapy. However, a variety of important cancer biomarkers have not been explored in searching of new and efficient targeted delivery systems. Uracil degradation glycosylase and human apurinic/apyrimidinic endonuclease are significantly more active in cancer cells. Here, we developed uracil-modified DNA nanotubes that can deliver drugs to tumor cells through an enzyme-induced disassembly process. Although the reaction of these enzymes on their natural DNA substrates has been established, their reactivity on self-assembled nanostructures of nucleic acids is not well understood. We leveraged molecular dynamic simulation based on coarse-grained model to forecast the enzyme reactivity on different DNA designs. The experimental data are highly consistent with the simulation results. It is the first example of molecule simulation being used to guide the design of enzyme-responsive DNA nano-delivery systems. Importantly, we found that the efficiency of drug release from the nanotubes can be regulated by tuning the positions of uracil modification. The DNA nanotubes equipped with cancer-specific aptamer AS1411 are used to deliver doxorubicin to tumor-bearing mice not only effectively inhibiting tumor growth but also protecting major organs from drug-caused damage. We believe that this work provides new knowledge on and insights into future design of enzyme-responsive DNA-based nanocarriers for drug delivery.
    Keywords:  DNA nanotechnology; DNA-modifying enzyme; MD simulation; base excision repair (BER) pathway; stimuli-responsive drug delivery
  5. ACS Nano. 2022 Jul 21.
      Overproduction of reactive oxygen species (ROS), a key characteristic of inflammatory bowel disease (IBD), is responsible for dysregulation of signal transduction, inflammatory response, and DNA damage, which ultimately leads to disease progression and deterioration. Thus, ROS scavenging has become a promising strategy to navigate IBD. Inspired by the targeting capability of hyaluronic acid (HA) to CD44-overexpressed inflammatory cells together with the redox regulation capacity of diselenide compounds, we developed an oral nanoformulation, i.e., diselenide-bridged hyaluronic acid nanogel (SeNG), with a view to treat colitis through a ROS scavenging mechanism. Our data demonstrated that SeNG specifically accumulated in colitis tissue that was mediated by highly efficient CD44-HA interaction. This has allowed us to demonstrate a significant anti-inflammatory effect in an acute colitis mouse model induced by dextran sulfate sodium and trinitrobenzenesulfonic acid. Mechanistically, we continued to show SeNG reduced the ROS level via both direct elimination and up-regulation of the Nrf2/HO-1 signal pathway. Collectively, our work provides proof-of-principle evidence for a SeNG-mediated nano-antioxidant strategy, by which colitis could be effectively managed.
    Keywords:  Nrf-2/HO-1; ROS scavenger; colitis; diselenide-bridged nanogel; nano-antioxidant
  6. ACS Appl Bio Mater. 2022 Jul 17.
      Multidrug resistance (MDR) in cancer cells is a substantial limitation to the success of chemotherapy. The spatio-temporal controlled gene-chemo therapeutics strategy is expected to surmount the limitation of MDR. We herein develop a DNA nanocomplex to achieve intrinsic stimuli-responsive spatio-temporal controlled gene-chemo drug delivery, overcoming MDR of cancer cells. The drug delivery system consisted of a restriction endonuclease (HhaI)-degradable DNA hydrogel layer, an acid-responsive HhaI nanocapsule (HhaI-GDA), and a glutathione (GSH)-sensitive dendritic mesoporous organosilica nanoparticle (DMON). The DNA hydrogel layer consisted of a DNA network formed through interfacial assembly from ultralong single-stranded DNA (ssDNA), which contained multiple tandem repeated antisense oligonucleotides (ASOs). DMON had dendritic mesopores for enhanced loading of anti-tumor drug doxorubicin (DOX). Upon cellular uptake of the DNA nanocomplex, the GDA shell was degraded at a lysosomal microenvironment, and the activity of HhaI was activated, leading to accurate cleavage ultralong ssDNA to release ASO as gene drugs, which down-regulated the expression of MDR-related P glycoprotein. Spatio-temporal sequentially, DMONs containing disulfide bonds responded to intracellular GSH to release DOX for enhanced chemotherapy.
    Keywords:  DNA nanotechnology; antisense oligonucleotide; chemotherapy; gene therapy; multidrug resistance
  7. Sci Adv. 2022 Jul 15. 8(28): eabq1905
      The octopus couples controllable adhesives with intricately embedded sensing, processing, and control to manipulate underwater objects. Current synthetic adhesive-based manipulators are typically manually operated without sensing or control and can be slow to activate and release adhesion, which limits system-level manipulation. Here, we couple switchable, octopus-inspired adhesives with embedded sensing, processing, and control for robust underwater manipulation. Adhesion strength is switched over 450× from the ON to OFF state in <50 ms over many cycles with an actively controlled membrane. Systematic design of adhesive geometry enables adherence to nonideal surfaces with low preload and independent control of adhesive strength and adhesive toughness for strong and reliable attachment and easy release. Our bio-inspired nervous system detects objects and autonomously triggers the switchable adhesives. This is implemented into a wearable glove where an array of adhesives and sensors creates a biomimetic adhesive skin to manipulate diverse underwater objects.
  8. Proc Natl Acad Sci U S A. 2022 Jul 12. 119(28): e2201423119
      Treatments for advanced and recurrent ovarian cancer remain a challenge due to a lack of potent, selective, and effective therapeutics. Here, we developed the basis for a transformative anticancer strategy based on anthrax toxin that has been engineered to be selectively activated by the catalytic power of zymogen-activating proteases on the surface of malignant tumor cells to induce cell death. Exposure to the engineered toxin is cytotoxic to ovarian tumor cell lines and ovarian tumor spheroids derived from patient ascites. Preclinical studies demonstrate that toxin treatment induces tumor regression in several in vivo ovarian cancer models, including patient-derived xenografts, without adverse side effects, supportive of progression toward clinical evaluation. These data lay the groundwork for developing therapeutics for treating women with late-stage and recurrent ovarian cancers, utilizing a mechanism distinct from current anticancer therapies.
    Keywords:  anthrax toxin; ascites; membrane-anchored serine proteases; metastatic ovarian cancer; prodrug
  9. Proc Natl Acad Sci U S A. 2022 Jul 19. 119(29): e2113180119
      The mutant form of the guanosine triphosphatase (GTPase) KRAS is a key driver in human tumors but remains a challenging therapeutic target, making KRASMUT cancers a highly unmet clinical need. Here, we report a class of bottlebrush polyethylene glycol (PEG)-conjugated antisense oligonucleotides (ASOs) for potent in vivo KRAS depletion. Owing to their highly branched architecture, these molecular nanoconstructs suppress nearly all side effects associated with DNA-protein interactions and substantially enhance the pharmacological properties of the ASO, such as plasma pharmacokinetics and tumor uptake. Systemic delivery to mice bearing human non-small-cell lung carcinoma xenografts results in a significant reduction in both KRAS levels and tumor growth, and the antitumor performance well exceeds that of current popular ASO paradigms, such as chemically modified oligonucleotides and PEGylation using linear or slightly branched PEG. Importantly, these conjugates relax the requirement on the ASO chemistry, allowing unmodified, natural phosphodiester ASOs to achieve efficacy comparable to that of chemically modified ones. Both the bottlebrush polymer and its ASO conjugates appear to be safe and well tolerated in mice. Together, these data indicate that the molecular brush-ASO conjugate is a promising therapeutic platform for the treatment of KRAS-driven human cancers and warrant further preclinical and clinical development.
    Keywords:  KRAS; NSCLC; antisense oligonucleotide; gene regulation; molecular brush
  10. Small. 2022 Jul 17. e2202663
      T cell exhaustion caused by mitochondrial dysfunction is the major obstacle of T cells-based cancer immunotherapy. Besides exhausted T cells, the insufficient major histocompatibility complex class I (MHC I) on tumor cells leads to inefficient T cell recognition of tumor cells, compromising therapeutic efficacy. Therapeutic platform to regulate T cell exhaustion and MHC I expression for boosting T cells-based cancer immunotherapy has not been realized up to date. Herein, an injectable hydrogel is designed to simultaneously tune T cell exhaustion and MHC I expression for amplified cancer immunotherapy. The hydrogel is in situ constructed in tumor site by utilizing oxidized sodium alginate-modified tumor cell membrane vesicle (O-TMV) as a gelator, where axitinib is encapsulated in the lipid bilayer of O-TMV while 4-1BB antibody and proprotein convertase subtilisin/kexin type 9 inhibitor PF-06446846 nanoparticles are present in the cavities of hydrogel. After immune response trigged by O-TMV antigen, the 4-1BB antibody-promoted T cell mitochondrial biogenesis and the axitinib-lowered hypoxia synergistically reverse T cell exhaustion while the PF-06446846-amplified MHC I expression facilitates T cell recognition of tumor cells, demonstrating a powerful immunotherapeutic efficacy. This strategy on reprograming T cell exhaustion and improving T cell potency offers new concept for T cells-based cancer immunotherapy.
    Keywords:  T cell exhaustion; T cell recognition; hydrogels; immunotherapy; mitochondria
  11. Adv Healthc Mater. 2022 Jul 18. e2200809
      Nanozymes with multienzyme-mimicking activities have shown great potential in cancer therapy due to their ability to modulate the complex tumor microenvironment (TME). Herein, we developed a second near-infrared (NIR-II) photothermal-nanocatalyst by decorating Bi2 Te3 nanosheets with ultrasmall Au/Pd bimetallic nanoparticles (Bi2 Te3 -Au/Pd) to reverse the immunosuppressive TME. The peroxidase (POD)-like, catalase (CAT)-like activities, and glutathione (GSH) consumption capacity of Au/Pd modulated the TME by disrupting the intracellular redox homeostasis and relieving hypoxia in the TME. Notably, the amplified oxidative stress induced the accumulation of lipid hydroperoxides (LPO) for enhanced ferroptosis. Moreover, upon NIR-II photoirradiation at 1064 nm, the localized heat generated by Bi2 Te3 not only directly ablated the cancer cells but also enhanced the Au/Pd-mediated catalysis-mediated cancer therapy. Furthermore, both in vitro and in vivo studies confirmed that the Bi2 Te3 -Au/Pd nanocatalysts (BAP NCs) could effectively suppress tumour growth by inducing immunogenic cell death (ICD), and suppressing metastasis and recurrence by the synergistic treatment. Overall, this study provides a promising theranostic strategy for effective tumor inhibition. This article is protected by copyright. All rights reserved.
    Keywords:  NIR-II photothermal therapy; immune response; nanozyme; oxidative stress; reactive oxygen species
  12. Nat Commun. 2022 Jul 16. 13(1): 4137
      Nanoparticle elasticity is crucial in nanoparticles' physiological fate, but how this occurs is largely unknown. Using core-shell nanoparticles with a same PEGylated lipid bilayer shell yet cores differing in elasticity (45 kPa - 760 MPa) as models, we isolate the effects of nanoparticle elasticity from those of other physiochemical parameters and, using mouse models, observe a non-monotonic relationship of systemic circulation lifetime versus nanoparticle elasticity. Incubating our nanoparticles in mouse plasma provides protein coronas varying non-monotonically in composition depending on nanoparticle elasticity. Particularly, apolipoprotein A-I (ApoA1) is the only protein whose relative abundance in corona strongly correlates with our nanoparticles' blood clearance lifetime. Notably, similar results are observed when above nanoparticles' PEGylated lipid bilayer shell is changed to be non-PEGylated. This work unveils the mechanisms by which nanoparticle elasticity affects nanoparticles' physiological fate and suggests nanoparticle elasticity as a readily tunable parameter in future rational exploiting of protein corona.
  13. ACS Nano. 2022 Jul 22.
      Liquid-liquid phase separation (LLPS) is a common phenomenon underlying the formation of dynamic membraneless organelles in biological cells, which are emerging as major players in controlling cellular functions and health. The bottom-up synthesis of biomolecular liquid systems with simple constituents, like nucleic acids and peptides, is useful to understand LLPS in nature as well as to develop programmable means to build new amorphous materials with properties matching or surpassing those observed in natural condensates. In particular, understanding which parameters determine condensate growth kinetics is essential for the synthesis of condensates with the capacity for active, dynamic behaviors. Here we use DNA nanotechnology to study artificial liquid condensates through programmable star-shaped subunits, focusing on the effects of changing subunit size. First, we show that LLPS is achieved in a 6-fold range of subunit size. Second, we demonstrate that the rate of growth of condensate droplets scales with subunit size. Our investigation is supported by a general model that describes how coarsening and coalescence are expected to scale with subunit size under ideal assumptions. Beyond suggesting a route toward achieving control of LLPS kinetics via design of subunit size in synthetic liquids, our work suggests that particle size may be a key parameter in biological condensation processes.
    Keywords:  DNA nanotechnology; biomolecular materials; condensates; phase separation; programmable materials
  14. Small. 2022 Jul 20. e2203292
      An effective therapeutic strategy against methicillin-resistant Staphylococcus aureus (MRSA) that does not promote further drug resistance is highly desirable. While phototherapies have demonstrated considerable promise, their application toward bacterial infections can be limited by negative off-target effects to healthy cells. Here, a smart targeted nanoformulation consisting of a liquid perfluorocarbon core stabilized by a lipid membrane coating is developed. Using vancomycin as a targeting agent, the platform is capable of specifically delivering an encapsulated photosensitizer along with oxygen to sites of MRSA infection, where high concentrations of pore-forming toxins trigger on-demand payload release. Upon subsequent near-infrared irradiation, local increases in temperature and reactive oxygen species effectively kill the bacteria. Additionally, the secreted toxins that are captured by the nanoformulation can be processed by resident immune cells to promote multiantigenic immunity that protects against secondary MRSA infections. Overall, the reported approach for the on-demand release of phototherapeutic agents into sites of infection could be applied against a wide range of high-priority pathogens.
    Keywords:  MRSA infection; antivirulence therapy; in situ vaccination; nanotoxoid; photothermal/photodynamic therapy; pore-forming toxin; sphingomyelin liposome
  15. Nat Commun. 2022 Jul 21. 13(1): 4197
      Metagenomic DNA sequencing is a powerful tool to characterize microbial communities but is sensitive to environmental DNA contamination, in particular when applied to samples with low microbial biomass. Here, we present Sample-Intrinsic microbial DNA Found by Tagging and sequencing (SIFT-seq) a metagenomic sequencing assay that is robust against environmental DNA contamination introduced during sample preparation. The core idea of SIFT-seq is to tag the DNA in the sample prior to DNA isolation and library preparation with a label that can be recorded by DNA sequencing. Any contaminating DNA that is introduced in the sample after tagging can then be bioinformatically identified and removed. We applied SIFT-seq to screen for infections from microorganisms with low burden in blood and urine, to identify COVID-19 co-infection, to characterize the urinary microbiome, and to identify microbial DNA signatures of sepsis and inflammatory bowel disease in blood.
  16. Angew Chem Int Ed Engl. 2022 Jul 22.
      Endosomal entrapment has remained the major bottleneck for cytosolic delivery of nanoparticle-based delivery systems. Uncovering fundamentally new pathways for endosomal escape is therefore highly sought. Herein, we report that disulfide bonds can enhance endosomal escape through contacts with cellular exofacial thiols, in addition to facilitating cellular uptake. Our results are supported through comparative analysis of polymeric nanogels with variable accessibility to disulfide bonds by placing these functionalities at the core or the shell of the nanogels. The findings here inform future chemical design of delivery vehicles.
    Keywords:  Disulfide bond; Endosomal Escape; Endosomal entrapment; Polymeric nanogel
  17. Proc Natl Acad Sci U S A. 2022 Jul 19. 119(29): e2203074119
      Adhesives typically fall into two categories: those that have high but irreversible adhesion strength due to the formation of covalent bonds at the interface and are slow to deploy, and others that are fast to deploy and the adhesion is reversible but weak in strength due to formation of noncovalent bonds. Synergizing the advantages from both categories remains challenging but pivotal for the development of the next generation of wound dressing adhesives. Here, we report a fast and reversible adhesive consisting of dynamic boronic ester covalent bonds, formed between poly(vinyl alcohol) (PVA) and boric acid (BA) for potential use as a wound dressing adhesive. Mechanical testing shows that the adhesive film has strength in shear of 61 N/cm2 and transcutaneous adhesive strength of 511 N/cm2, generated within 2 min of application. Yet the film can be effortlessly debonded when exposed to excess water. The mechanical properties of PVA/BA adhesives are tunable by varying the cross-linking density. Within seconds of activation by water, the surface boronic ester bonds in the PVA/BA film undergo fast debonding and instant softening, leading to conformal contact with the adherends and reformation of the boronic ester bonds at the interface. Meanwhile, the bulk film remains dehydrated to offer efficient load transmission, which is important to achieve strong adhesion without delamination at the interface. Whether the substrate surface is smooth (e.g., glass) or rough (e.g., hairy mouse skin), PVA/BA adhesives demonstrate superior adhesion compared to the most widely used topical skin adhesive in clinical medicine, Dermabond.
    Keywords:  adhesives; dynamic covalent bonds; hydrogel; reversible; wound dressing