bims-drudre Biomed News
on Targeted drug delivery and programmed release mechanisms
Issue of 2022‒04‒10
eleven papers selected by
Ceren Kimna
Technical University of Munich

  1. Sci Adv. 2022 Apr 08. 8(14): eabn1701
      There is an increasingly growing demand for nonantibiotic strategies to overcome drug resistance in bacterial biofilm infections. Here, a novel "gas-sensitized hyperthermia" strategy is proposed for appreciable bacteria killing by the smart design of a metal-organic framework (MOF)-sealed Prussian blue-based nanocarrier (MSDG). Once the biofilm microenvironment (BME) is reached, the acidity-activated MOF degradation allows the release of diallyl trisulfide and subsequent glutathione-responsive generation of hydrogen sulfide (H2S) gas. Upon near-infrared irradiation, H2S-sensitized hyperthermia arising from MSDG can efficiently eliminate biofilms through H2S-induced extracellular DNA damage and heat-induced bacterial death. The generated H2S in the biofilm can stimulate the polarization of macrophages toward M2 phenotype for reshaping immune microenvironment. Subsequently, the secretion of abundant regeneration-related cytokines from M2 macrophages accelerates tissue regeneration by reversing the infection-induced pro-inflammatory environment in an implant-related infection model. Collectively, such BME-responsive nano-antibacterials can achieve biofilm-specific H2S-sensitized thermal eradiation and immunomodulatory tissue remodeling, thus realizing the renaissance of precision treatment of refractory implant-related infections.
  2. Nat Commun. 2022 Apr 08. 13(1): 1928
      Mechanical breathing motions have a fundamental function in lung development and disease, but little is known about how they contribute to host innate immunity. Here we use a human lung alveolus chip that experiences cyclic breathing-like deformations to investigate whether physical forces influence innate immune responses to viral infection. Influenza H3N2 infection of mechanically active chips induces a cascade of host responses including increased lung permeability, apoptosis, cell regeneration, cytokines production, and recruitment of circulating immune cells. Comparison with static chips reveals that breathing motions suppress viral replication by activating protective innate immune responses in epithelial and endothelial cells, which are mediated in part through activation of the mechanosensitive ion channel TRPV4 and signaling via receptor for advanced glycation end products (RAGE). RAGE inhibitors suppress cytokines induction, while TRPV4 inhibition attenuates both inflammation and viral burden, in infected chips with breathing motions. Therefore, TRPV4 and RAGE may serve as new targets for therapeutic intervention in patients infected with influenza and other potential pandemic viruses that cause life-threatening lung inflammation.
  3. Small. 2022 Apr 03. e2200165
      Diabetic wound healing remains challenging owing to the risk for bacterial infection, hypoxia, excessive glucose levels, and oxidative stress. Glucose-activated cascade reactions can consume glucose and eradicate bacteria, avoiding the direct use of hydrogen peroxide (H2 O2 ) and wound pH restriction on peroxidase-like activity. However, the anoxic microenvironment in diabetic wounds impedes the cascade reaction due to the oxygen (O2 ) dependence of glucose oxidation. Herein, defect-rich molybdenum disulfide nanosheets loaded with bovine serum albumin-modified gold nanoparticle (MoS2 @Au@BSA NSs) heterostructures are designed and anchored onto injectable hydrogels to promote diabetic wound healing through an O2 self-supplying cascade reaction. BSA decoration decreases the particle size of Au, increasing the activity of multiple enzymes. Glucose oxidase-like Au catalyzes the oxidation of glucose into gluconic acid and H2 O2 , which is transformed into a hydroxyl radical (•OH) catalyzed by peroxidase-like MoS2 @Au@BSA to eradicate bacteria. When the wound pH reaches an alkalescent condition, MoS2 @Au@BSA mimicks superoxide dismutase to transform superoxide anions into O2 and H2 O2 , and decomposes endogenous and exogenous H2 O2 into O2 via catalase-like mechanisms, reducing oxidative stress, alleviating hypoxia, and facilitating glucose oxidation. The MoS2 @Au@BSA nanozyme-anchored injectable hydrogel, composed of oxidized dextran and glycol chitosan crosslinked through a Schiff base, significantly accelerates diabetic wound healing.
    Keywords:  O 2 self-supplying; cascade reactions; defects; diabetic wound healing; nanozymes
  4. Nat Commun. 2022 Apr 06. 13(1): 1845
      Immunosuppressive cells residing in the tumor microenvironment, especially tumor associated macrophages (TAMs), hinder the infiltration and activation of T cells, limiting the anti-cancer outcomes of immune checkpoint blockade. Here, we report a biocompatible alginate-based hydrogel loaded with Pexidartinib (PLX)-encapsulated nanoparticles that gradually release PLX at the tumor site to block colony-stimulating factor 1 receptors (CSF1R) for depleting TAMs. The controlled TAM depletion creates a favorable milieu for facilitating local and systemic delivery of anti-programmed cell death protein 1 (aPD-1) antibody-conjugated platelets to inhibit post-surgery tumor recurrence. The tumor immunosuppressive microenvironment is also reprogrammed by TAM elimination, further promoting the infiltration of T cells into tumor tissues. Moreover, the inflammatory environment after surgery could trigger the activation of platelets to facilitate the release of aPD-1 accompanied with platelet-derived microparticles binding to PD-1 receptors for re-activating T cells. All these results collectively indicate that the immunotherapeutic efficacy against tumor recurrence of both local and systemic administration of aPD-1 antibody-conjugated platelets could be strengthened by local depletion of TAMs through the hydrogel reservoir.
  5. Angew Chem Int Ed Engl. 2022 Apr 06.
      Cellular functions in living cells are facilitated by diffusible molecular signals that are sensed and processed by receiver cells and can control intracellular pathways. Protocells containing enzyme-driven biomolecular circuits that can process and exchange information offer a promising approach for mimicking cellular features and developing molecular information platforms for use in molecular data storage and diagnostics. Here, we employ synthetic transcriptional circuits together with CRISPR/Cas-based DNA processing inside semipermeable protein-polymer microcompartments. We first establish a transcriptional protocell that can be activated by external DNA strands and produce functional RNA aptamers. Subsequently, we engineer the transcriptional module to generate short RNA strands functioning as diffusive signals that can be sensed by neighboring protocells and trigger the activation of internalized DNA probes or localization of Cas nucleases. Our results highlight the opportunities to combine CRISPR/Cas machinery and DNA nanotechnology for protocellular communication and provide a step towards the development of protocells capable of distributed molecular information processing.
    Keywords:  DNA; Molecular Communication; Synthetic Protocells; enzymes
  6. ACS Appl Mater Interfaces. 2022 Apr 07.
      Microstructured surfaces with stimuli-responsive performances have aroused great attention in recent years, but it still remains a significant challenge to endow surfaces with precisely controlled morphological changes in microstructures, so as to get the precise control of regional properties (e.g., friction, adhesion). Herein, a kind of carbonyl iron particle-doped shape memory polyurethane micropillar with precisely controllable morphological changes is realized, upon remote near-infrared light (NIR) irradiation. Owing to the reversible transition of micropillars between bent and upright states, the micro-structured surface exhibits precisely controllable low-to-high friction transitions, together with the changes of friction coefficient ranging from ∼0.8 to ∼1.2. Hence, the changes of the surface friction even within an extremely small area can be precisely targeted, under local NIR laser irradiation. Moreover, the water droplet adhesion force of the surface can be reversibly switched between ∼160 and ∼760 μN, demonstrating the application potential in precisely controllable wettability. These features indicate that the smart stimuli-responsive micropillar arrays would be amenable to a variety of applications that require remote, selective, and on-demand responses, such as a refreshable Braille display system, micro-particle motion control, lab-on-a-chip, and microfluidics.
    Keywords:  photothermal effect; precisely controllable; shape memory nanocomposite; tunable adhesion; tunable friction
  7. Adv Mater. 2022 Apr 07. e2109764
      Biofouling on the surface of implanted medical devices and biosensors severely hinders device functionality and drastically shortens device lifetime. Poly(ethylene glycol) and zwitterionic polymers are currently considered "gold standard" device coatings to reduce biofouling. To discover novel anti-biofouling materials, we created a combinatorial library of polyacrylamide-based copolymer hydrogels and screened their ability to prevent fouling from serum and platelet-rich plasma in a high-throughput parallel assay. We found certain non-intuitive copolymer compositions exhibit superior anti-biofouling properties over current gold standard materials, and employed machine learning to identify key molecular features underpinning their performance. For validation, we coated the surfaces of electrochemical biosensors with our hydrogels and evaluated their anti-biofouling performance in vitro and in vivo in rodent models. Our copolymer hydrogels preserved device function and enabled continuous measurements of a small-molecule drug in vivo better than gold standard coatings. The novel methodology we describe enables the discovery of anti-biofouling materials that can extend the lifetime of real-time in vivo sensing devices. This article is protected by copyright. All rights reserved.
    Keywords:  anti-fouling; biosensors; devices; hydrogels; polymers
  8. Adv Healthc Mater. 2022 Apr 04. e2200011
      Mechanically tunable hydrogels are attractive platforms for three-dimensional cell culture, as hydrogel stiffness plays an important role in cell behavior. Traditionally, hydrogel stiffness has been controlled through altering either the polymer concentration or the stoichiometry between crosslinker reactive groups. Here, we present an alternative strategy based upon tuning the hydrophilicity of an elastin-like protein (ELP). ELPs undergo a phase transition that leads to protein aggregation at increasing temperatures. We hypothesize that increasing this transition temperature through bioconjugation with azide-containing molecules of increasing hydrophilicity will allow direct control of the resulting gel stiffness by making the crosslinking groups more accessible. These azide-modified ELPs are crosslinked into hydrogels with bicyclononyne-modified hyaluronic acid (HA-BCN) using bioorthogonal, click chemistry, resulting in hydrogels with tunable storage moduli (100-1000 Pa). Human mesenchymal stromal cells, human umbilical vein endothelial cells, and human neural progenitor cells are all observed to alter their cell morphology when encapsulated within hydrogels of varying stiffness. Taken together, we demonstrate the use of protein hydrophilicity as a lever to tune hydrogel mechanical properties. These hydrogels have tunable moduli over a stiffness range relevant to soft tissues, support the viability of encapsulated cells, and modify cell spreading as a consequence of gel stiffness. This article is protected by copyright. All rights reserved.
    Keywords:  click chemistry; elastin-like protein; hyaluronic acid; lower critical solution temperature; three-dimensional culture
  9. Proc Natl Acad Sci U S A. 2022 Apr 12. 119(15): e2110987119
      SignificanceAntigen-specific immunotherapy may be improved by focusing on epitopes that are disease-relevant and known to be presented on an individual's human leukocyte antigen (HLA) haplotype, while targeting T cells across multiple antigens and including specific neoepitopes that are not present in protein antigens and/or not produced beyond inflamed sites. Here, we provide proof of principle that such a strategy applied to tolerogenic DNA vaccination is effective in a preclinical model of autoimmune diabetes, paving the way for precision medicine using endogenously encoded epitopes. It takes a minimum number of regular treatments to achieve a level of tolerance and regulation that is needed to limit insulitis and provide sustained protection before treatment may be discontinued or reduced in frequency.
    Keywords:  DNA vaccine; autoimmune diabetes; epitope; precision medicine; tolerance
  10. Adv Mater. 2022 Apr 06. e2201051
      Cancer is one of the most intractable diseases owing to its high mortality rate and lack of effective diagnostic and treatment tools. Advancements in micro/nanorobot (MNR)-assisted sensing, imaging, and therapeutics offer unprecedented opportunities to develop MNR-based cancer theragnostic platforms. Unlike ordinary nanoparticles which exhibit Brownian motion in biofluids, MNRs overcome viscous resistance in an ultralow Reynolds number (Re<<1) environment by effective self-propulsion. This unique locomotion property has motivated the advanced design and functionalization of MNRs as a basis for next-generation cancer therapy platforms, which offer the potential for precise distribution and improved permeation of therapeutic agents. Enhanced barrier penetration, imaging-guided operation, and biosensing have additionally been studied to enable the promising cancer-related applications of MNRs. This review comprehensively addresses recent advances in MNR-based cancer therapy, including in actuation engines, diagnostics, medical imaging, and targeted drug delivery; we highlight promising research opportunities that could have a profound impact on cancer therapy over the next decade. This article is protected by copyright. All rights reserved.
    Keywords:  drug delivery; medical imaging; micro/nano robotic; tumor diagnosis; tumor therapy
  11. Anal Chem. 2022 Apr 05.
      The desire for a cancer theranostic system with simultaneously accurate diagnosis and efficient therapy is undeniably interminable. Heretofore, theranostic systems with simple components were designed for cancer theranostics but with confined accuracy of diagnosis and side effects of administered drugs. Here, we report an activatable theranostic system for simultaneously imaging dual cancer-related RNAs, mRNA Bcl-2 and piRNA-36026, and combined gene-chemotherapy through the target-induced intracellular disassembly of DNA tetrahedron. Briefly, five customized oligonucleotides are used to assemble the functionalized DNA tetrahedron. The relevant functional nucleic acids, including the antisequence of mRNA Bcl-2, the antisequence of piRNA-36026, and aptamer AS1411, are designed in the customized oligonucleotides with the signal reporters Cy3 and Cy5. Doxorubicin (DOX) is loaded in the functionalized DNA tetrahedron by inlaying between cytosine and guanine to form the activatable cancer theranostic system. The activatable cancer theranostic system is able to recognize MCF-7 cells by aptamer AS1411 and then enter the cells. In the presence of targets, the antisequences in the activatable cancer theranostic system hybridize with intracellular mRNA Bcl-2 and piRNA-36026, leading to the fluorescence signal recovery of Cy3 and Cy5 and the downregulation of two targets in the cytoplasm as well as the consequent apoptosis of MCF-7 cells in the form of gene therapy. Interestingly, as the antisequences are designed in the assembly strands, the hybridization between targets and the antisequences results in the disassembly of the activatable cancer theranostic system and the release of DOX as well as sequential chemotherapy. Advantageously, the activatable cancer theranostic system can achieve imaging of dual cancer-related RNAs with an imaging time window as long as 15 h and exhibit an obvious therapeutic effect in vivo. Therefore, this work is in furtherance of exploration for activatable cancer theranostic systems with high accuracy and efficiency and sheds new light on the development of precision medicine.