bims-drudre Biomed News
on Targeted drug delivery and programmed release mechanisms
Issue of 2022‒02‒13
seven papers selected by
Ceren Kimna
Technical University of Munich

  1. Adv Mater. 2022 Feb 06. e2200115
      Due to the wet and dynamic environment of the oral cavity, the healing of intraoral wounds, such as tooth extraction wounds, requires stable and firm wound dressings. In clinical practice, cotton balls and gauze, sponge plugs, or sutures are used to treat extraction wounds, but none of these means can continuously isolate the wound from the intraoral environment and provide ideal healing conditions. Herein, inspired by the natural extracellular matrix, a family of wound dressings was developed for intraoral wound repair. Infiltrating a ductile long-chain hydrogel network into a prefabricated, sturdy macromolecular meshwork and in situ crosslinking endowed the composite hydrogel with controllable swelling behaviors and robust mechanical properties. The macromolecular meshwork functioned as the backbone to support the composite and restricts the swelling of the long-chain hydrogel network. In vitro tests verified that this dressing could provide durable protection for intraoral wounds against complex irritations. Furthermore, accelerated wound healing occurred when the dressing was applied in vivo on a canine tooth extraction model due to the effective reduction of acute inflammation. These results suggest the bioinspired hydrogel has great potential for application as an intraoral dressing. This article is protected by copyright. All rights reserved.
    Keywords:  anti-swelling; biomimetic materials; hydrogel; intraoral wound dressings; tooth extraction
  2. Nat Commun. 2022 Feb 11. 13(1): 829
      Advances in synthetic biology permit the genetic encoding of synthetic chemistries at monomeric precision, enabling the synthesis of programmable proteins with tunable properties. Bacterial pili serve as an attractive biomaterial for the development of engineered protein materials due to their ability to self-assemble into mechanically robust filaments. However, most biomaterials lack electronic functionality and atomic structures of putative conductive proteins are not known. Here, we engineer high electronic conductivity in pili produced by a genomically-recoded E. coli strain. Incorporation of tryptophan into pili increased conductivity of individual filaments >80-fold. Computationally-guided ordering of the pili into nanostructures increased conductivity 5-fold compared to unordered pili networks. Site-specific conjugation of pili with gold nanoparticles, facilitated by incorporating the nonstandard amino acid propargyloxy-phenylalanine, increased filament conductivity ~170-fold. This work demonstrates the sequence-defined production of highly-conductive protein nanowires and hybrid organic-inorganic biomaterials with genetically-programmable electronic functionalities not accessible in nature or through chemical-based synthesis.
  3. Nat Biotechnol. 2022 Feb 10.
      Recruiting endogenous adenosine deaminases using exogenous guide RNAs to edit cellular RNAs is a promising therapeutic strategy, but editing efficiency and durability remain low using current guide RNA designs. In this study, we engineered circular ADAR-recruiting guide RNAs (cadRNAs) to enable more efficient programmable adenosine-to-inosine RNA editing without requiring co-delivery of any exogenous proteins. Using these cadRNAs, we observed robust and durable RNA editing across multiple sites and cell lines, in both untranslated and coding regions of RNAs, and high transcriptome-wide specificity. Additionally, we increased transcript-level specificity for the target adenosine by incorporating interspersed loops in the antisense domains, reducing bystander editing. In vivo delivery of cadRNAs via adeno-associated viruses enabled 53% RNA editing of the mPCSK9 transcript in C57BL/6J mice livers and 12% UAG-to-UGG RNA correction of the amber nonsense mutation in the IDUA-W392X mouse model of mucopolysaccharidosis type I-Hurler syndrome. cadRNAs enable efficient programmable RNA editing in vivo with diverse protein modulation and gene therapeutic applications.
  4. Nat Cancer. 2022 Feb 10.
      Translating preclinical studies to effective treatment protocols and identifying specific therapeutic responses in individuals with cancer is challenging. This may arise due to the complex genetic makeup of tumor cells and the impact of their multifaceted tumor microenvironment on drug response. To find new clinically relevant drug combinations for colorectal cancer (CRC), we prioritized the top five synergistic combinations from a large in vitro screen for ex vivo testing on 29 freshly resected human CRC tumors and found that only the combination of mitogen-activated protein kinase kinase (MEK) and proto-oncogene tyrosine-protein kinase Src (Src) inhibition was effective when tested ex vivo. Pretreatment phosphorylated Src (pSrc) was identified as a predictive biomarker for MEK and Src inhibition only in the absence of KRASG12 mutations. Overall, we demonstrate the potential of using ex vivo platforms to identify drug combinations and discover MEK and Src dual inhibition as an effective drug combination in a predefined subset of individuals with CRC.
  5. Proc Natl Acad Sci U S A. 2022 Feb 15. pii: e2112696119. [Epub ahead of print]119(7):
      Lysine-specific demethylase 6A (KDM6A), also named UTX, is frequently mutated in bladder cancer (BCa). Although known as a tumor suppressor, KDM6A's therapeutic potential in the metastasis of BCa remains elusive. It also remains difficult to fulfill the effective up-regulation of KDM6A levels in bladder tumor tissues in situ to verify its potential in treating BCa metastasis. Here, we report a mucoadhesive messenger RNA (mRNA) nanoparticle (NP) strategy for the intravesical delivery of KDM6A-mRNA in mice bearing orthotopic Kdm6a-null BCa and show evidence of KDM6A's therapeutic potential in inhibiting the metastasis of BCa. Through this mucoadhesive mRNA NP strategy, the exposure of KDM6A-mRNA to the in situ BCa tumors can be greatly prolonged for effective expression, and the penetration can be also enhanced by adhering to the bladder for sustained delivery. This mRNA NP strategy is also demonstrated to be effective for combination cancer therapy with other clinically approved drugs (e.g., elemene), which could further enhance therapeutic outcomes. Our findings not only report intravesical delivery of mRNA via a mucoadhesive mRNA NP strategy but also provide the proof-of-concept for the usefulness of these mRNA NPs as tools in both mechanistic understanding and translational study of bladder-related diseases.
    Keywords:  KDM6A; bladder cancer; elemene; intravesical delivery; mRNA nanoparticles
  6. Adv Mater. 2022 Feb 11. e2107506
      Idiopathic pulmonary fibrosis (IPF), a lethal respiratory disease with few treatment options, occurs due to repetitive microinjuries to alveolar epithelial cells (AECs) and progresses with an overwhelming deposition of extracellular matrix (ECM), ultimately resulting in fibrotic scars and destroyed alveolar architecture. Here, an inhaled ribosomal protein-based mRNA nanoformulation is reported for clearing the intrapulmonary ECM and re-epithelializing the disrupted alveolar epithelium, thereby reversing established fibrotic foci in IPF. The nanoformulation is sequentially assembled by a ribosomal protein-condensed mRNA core, a bifunctional peptide-modified corona and keratinocyte growth factor (KGF) with a PEGylated shielding shell. When inhaled via a nebulizer, the nanoformulations carried by microdrops are deposited in alveoli, and penetrate into fibrotic foci, where the outer KGFs are detached after matrix metalloproteinase 2 (MMP2) triggering. The RGD motif-grafted cores then expose and specifically target the integrin-elevated cells for the intracellular delivery of mRNA. Notably, repeated inhalation of the nanoformulations accelerates the clearance of locoregional collagen by boosting the intralesional expression of MMP13 and alveolar re-epithelialization mediated by KGFs, which synergistically ameliorates the lung function of a bleomycin-induced murine model. Therefore, our work provides an alternative mRNA-inhaled delivery strategy that shows great potential for the treatment of IPF. This article is protected by copyright. All rights reserved.
    Keywords:  cationic ribosomal protein; idiopathic pulmonary fibrosis; inhalation; messenger RNA; reversing fibrotic foci
  7. Adv Mater. 2022 Feb 08. e2110364
      Sonodynamic therapy (SDT) exhibits high tissue penetration and negligible radiation damage to normal tissues, and thus emerges as a promising cancer therapeutic modality for glioblastoma (GBM). However, the blood-brain barrier (BBB) and hypoxic microenvironment greatly limit the SDT efficiency. In this work, a biodegradable nanoplatform (termed as CSI) was fabricated by encapsulating catalase (CAT) into silica nanoparticles (CAT@SiO2 ) for tumor hypoxia relief, and then loaded with the sonosensitizer indocyanine green (ICG). Inspired by the ability of macrophages to cross the BBB, CSI was further coated with AS1411 aptamer-modified macrophage exosomes to form CSI@Ex-A, which possessed efficient BBB penetration and good cancer cell-targeting capability. After tumor cell endocytosis, highly expressed glutathione (GSH) triggeres biodegradation of the nanoplatform and the released CAT catalyzes hydrogen peroxide (H2 O2 ) to produce O2 to relieve tumor hypoxia. The GSH depletion and O2 self-supplying effectively enhanced the SDT efficiency both in vitro and in vivo. In addition, the resulting CSI@Ex-A exhibited good biocompatibility and long circulation time. These findings demonstrate that CSI@Ex-A may serve as a competent nanoplatform for GBM therapy, with potential for clinical translation. This article is protected by copyright. All rights reserved.
    Keywords:  Sonodynamic therapy; biodegradable nanoplatform; blood-brain barrier; exosomes; glioblastoma