bims-drudre Biomed News
on Targeted drug delivery and programmed release mechanisms
Issue of 2021‒12‒12
eight papers selected by
Ceren Kimna
Technical University of Munich

  1. Angew Chem Int Ed Engl. 2021 Dec 05.
      Sequential control of exogenous chemical events inside cells is a promising way to regulate cell functions and fate. Herein we report a DNA nanocomplex containing cascade DNAzymes and promoter-like Zn-Mn-Ferrite (ZMF), achieving combined gene/chemo-dynamic therapy. The promoter-like ZMF decomposed in response to intratumoral glutathione to release a sufficient quantity of metal ions, thus promoting cascade DNA/RNA cleavage and free radical generation. Two kinds of DNAzymes were designed for sequential cascade enzymatic reaction, in which metal ions functioned as cofactors. The primary DNAzyme self-cleaved the DNA chain with Zn2+ as cofactor, and produced the secondary DNAzyme; the secondary DNAzyme afterwards cleaved the EGR-1 mRNA, and thus downregulated the expression of target EGR-1 protein, achieving DNAzyme-based gene therapy. Meanwhile, the released Zn2+, Mn2+ and Fe2+ induced Fenton/Fenton-like reactions, during which free radicals were catalytically generated and efficient chemo-dynamic therapy was achieved. In a breast cancer mouse model, the administration of DNA nanocomplex led to a significant therapeutic efficacy of tumor growth suppression.
    Keywords:  DNA nanotechnology; DNAzyme; Gene therapy; Rolling circle amplification; chemo-dynamic therapy
  2. Nat Commun. 2021 Dec 09. 12(1): 7162
      A key challenge for the effective treatment of gastrointestinal diseases including inflammatory bowel disease is to develop an orally administered drug delivery system capable of prolonged retention in the gastrointestinal tract. Herein we report a bioadhesive liquid coacervate based on hydrogen bonding-driven nanoparticle assembly. Free from electrostatic interactions, our fluid nanoparticle-assembled coacervate demonstrates significant pH- and salt-independent structural stability and forms a physically adhesive coating on a large surface area of intestinal tract with an extended residence time of more than 2 days to mediate the sustained release of preloaded water-soluble small molecule drugs in vivo. The orally administered drug-laden nanoparticle-assembled coacervate significantly mitigates the symptoms of inflammatory bowel disease, restores the diversity of gut microbiota, reduces systemic drug exposure, and improves the therapeutic efficacy in a rat acute colitis model compared with the oral administration of the same amount of drug in solution form. We suggest that the nanoparticle-assembled coacervate provides a promising drug delivery platform for management and treatment of numerous gastrointestinal diseases where controlled drug release with extended residence time is desired.
  3. Proc Natl Acad Sci U S A. 2021 Dec 14. pii: e2114842118. [Epub ahead of print]118(50):
      Vascular disease is a leading cause of morbidity and mortality in the United States and globally. Pathological vascular remodeling, such as atherosclerosis and stenosis, largely develop at arterial sites of curvature, branching, and bifurcation, where disturbed blood flow activates vascular endothelium. Current pharmacological treatments of vascular complications principally target systemic risk factors. Improvements are needed. We previously devised a targeted polyelectrolyte complex micelle to deliver therapeutic nucleotides to inflamed endothelium in vitro by displaying the peptide VHPKQHR targeting vascular cell adhesion molecule 1 (VCAM-1) on the periphery of the micelle. This paper explores whether this targeted nanomedicine strategy effectively treats vascular complications in vivo. Disturbed flow-induced microRNA-92a (miR-92a) has been linked to endothelial dysfunction. We have engineered a transgenic line (miR-92aEC-TG /Apoe-/- ) establishing that selective miR-92a overexpression in adult vascular endothelium causally promotes atherosclerosis in Apoe-/- mice. We tested the therapeutic effectiveness of the VCAM-1-targeting polyelectrolyte complex micelles to deliver miR-92a inhibitors and treat pathological vascular remodeling in vivo. VCAM-1-targeting micelles preferentially delivered miRNA inhibitors to inflamed endothelial cells in vitro and in vivo. The therapeutic effectiveness of anti-miR-92a therapy in treating atherosclerosis and stenosis in Apoe-/- mice is markedly enhanced by the VCAM-1-targeting polyelectrolyte complex micelles. These results demonstrate a proof of concept to devise polyelectrolyte complex micelle-based targeted nanomedicine approaches treating vascular complications in vivo.
    Keywords:  atherosclerosis; nanomedicine; nanoparticle; stenosis; vascular remodeling
  4. ACS Nano. 2021 Dec 07.
      Sowing malignant cells (the "seeds" of metastasis) to engraft secondary sites requires a conducive premetastatic niche (PMN, the "soil" of metastasis). Inflammation and tumor associated platelet (TAP) has been hijacked by primary tumors to induce PMN "soil" in distant organs, as well as facilitate the dissemination of "seeds". This study reports a combinatory strategy with activated platelet-targeting nanoparticles to aim at the dynamic process of entire cancer metastasis, which exerts robust antimetastasis efficacy by simultaneously inhibiting tumor inflammation and tumor-platelet crosstalk. Our results reveals that the PSN peptide (a P-selectin-targeting peptide) modification enriched the accumulation of nanoparticles in primary tumor, pulmonary PMN, and metastases via capturing activated platelet. Such characteristics contribute to the efficient inhibition on almost every crucial and consecutive step of the metastasis cascade by retarding epithelial-mesenchymal transition (EMT) progression within tumors, specifically blocking the tumor-platelet crosstalk to remove the platelets "protective shield" around disseminated "seeds", and reversing the inflammatory microenvironment to interfere with the "soil" formation. Consisting of inflammation inhibiting and TAP impeding nanoparticles, this approach prominently reduces various metastasis in abscopal lung, including spontaneous metastasis, disseminated tumor cells metastasis, and post-operative metastasis. This work provides a generalizable nanoplatform of parallel inflammation disturbance and tumor-TAP crosstalk blockade to resist metastatic tumors.
    Keywords:  activated platelets targeting; antimetastasis therapy; inflammation; nanoparticle; premetastatic niche; tumor-associated platelet
  5. Adv Mater. 2021 Dec 06. e2107875
      Colloidal crystal engineering with DNA has led to significant advances in bottom-up materials synthesis and a new way of thinking about fundamental concepts in chemistry. Here, programmable atom equivalents (PAEs), comprised of nanoparticles (the "atoms") functionalized with DNA (the "bonding elements"), are assembled through DNA hybridization into crystalline lattices. Unlike atomic systems, the "atom" (e.g., the nanoparticle shape, size, and composition) and the "bond" (e.g., the DNA length and sequence) can be tuned independently, yielding designer materials with unique catalytic, optical, and biological properties. In this review, nearly three decades of work that have contributed to the evolution of this class of programmable matter is chronicled, starting from the earliest examples based on gold-core PAEs, and then delineating how advances in synthetic capabilities, DNA design, and fundamental understanding of PAE-PAE interactions have led to new classes of functional materials that, in several cases, have no natural equivalent. This article is protected by copyright. All rights reserved.
    Keywords:  Colloidal crystal engineering; DNA; Nanoparticle; programmable atom equivalent; spherical nucleic acids
  6. ACS Nano. 2021 Dec 09.
      Virus-like nanoparticles are protein shells similar to wild-type viruses, and both aim to deliver their content into a cell. Unfortunately, the release mechanism of their cargo/genome remains elusive. Pores on the symmetry axes were proposed to enable the slow release of the viral genome. In contrast, cryo-EM images showed that capsids of nonenveloped RNA viruses can crack open and rapidly release the genome. We combined in vitro cryo-EM observations of the genome release of three viruses with coarse-grained simulations of generic virus-like nanoparticles to investigate the cargo/genome release pathways. Simulations provided details on both slow and rapid release pathways, including the success rates of individual releases. Moreover, the simulated structures from the rapid release pathway were in agreement with the experiment. Slow release occurred when interactions between capsid subunits were long-ranged, and the cargo/genome was noncompact. In contrast, rapid release was preferred when the interaction range was short and/or the cargo/genome was compact. These findings indicate a design strategy of virus-like nanoparticles for drug delivery.
    Keywords:  RNA virus; capsid; coarse-grained model; computer simulations; cryo-EM; genome release; virus-like nanoparticles
  7. Angew Chem Int Ed Engl. 2021 Dec 08.
      Herein, we report a universal boronate-affinity crosslinking-amplified dynamic light scattering (DLS) immunoassay for point-of-care (POC) glycoprotein detection in complex samples. This enhanced DLS immunoassay consists of two elements, i.e. , antibody-coated magnetic nanoparticles (MNP@mAb) for target capture and DLS signal transduction, and phenylboronic acid-based boronate affinity materials as crosslinking amplifiers. Upon the addition of targets, glycoproteins are first captured by MNP@mAb and amplified by target-induced crosslinking stemmed from the selective binding between the boronic acid ligand and cis -diol-containing glycoprotein, thereby resulting in a remarkably increased DLS signal in the average nanoparticle size. Benefiting from the multivalent binding and fast boronate affinity reaction between glycoproteins and crosslinkers, the proposed immunosensing strategy has achieved the ultrasensitive and rapid quantitative assay of glycoproteins at the fM level within 15 min. Overall, this work provides a promising and versatile design strategy for extending the DLS technique to detect glycoproteins even in the field or at POC.
    Keywords:  glycoproteins * boronate affinity * dynamic light scattering * immunoassay
  8. Nat Commun. 2021 Dec 09. 12(1): 7155
      Pyroptosis induced by the N-terminal gasdermin domain (GSDMNT) holds great potential for anti-tumor therapy. However, due to the extreme cytoxicity of GSDMNT, it is challenging to efficiently produce and deliver GSDMNT into tumor cells. Here, we report the development of two strategies to package recombinant adeno-associated virus (rAAV) expressing GSDMNT: 1) drive the expression of GSDMNT by a mammal specific promoter and package the virus in Sf9 insect cells to avoid its expression; 2) co-infect rAAV-Cre to revert and express the double-floxed inverted GSDMNT. We demonstrate that these rAAVs can induce pyroptosis and prolong survival in preclinical cancer models. The oncolytic-viruses induce pyroptosis and evoke a robust immune-response. In a glioblastoma model, rAAVs temporarily open the blood-brain barrier and recruit tumor infiltrating lymphocytes into the brain. The oncolytic effect is further improved in combination with anti-PD-L1. Together, our strategies efficiently produce and deliver GSDMNT into tumor cells and successfully induce pyroptosis, which can be exploited for anti-tumor therapy.