bims-drudre Biomed News
on Targeted drug delivery and programmed release mechanisms
Issue of 2021‒12‒05
twelve papers selected by
Ceren Kimna
Technical University of Munich

  1. Nat Mater. 2021 Dec 02.
      Engineered living materials could have the capacity to self-repair and self-replicate, sense local and distant disturbances in their environment, and respond with functionalities for reporting, actuation or remediation. However, few engineered living materials are capable of both responsivity and use in macroscopic structures. Here we describe the development, characterization and engineering of a fungal-bacterial biocomposite grown on lignocellulosic feedstocks that can form mouldable, foldable and regenerative living structures. We have developed strategies to make human-scale biocomposite structures using mould-based and origami-inspired growth and assembly paradigms. Microbiome profiling of the biocomposite over multiple generations enabled the identification of a dominant bacterial component, Pantoea agglomerans, which was further isolated and developed into a new chassis. We introduced engineered P. agglomerans into native feedstocks to yield living blocks with new biosynthetic and sensing-reporting capabilities. Bioprospecting the native microbiota to develop engineerable chassis constitutes an important strategy to facilitate the development of living biomaterials with new properties and functionalities.
  2. Adv Mater. 2021 Dec 02. e2106654
      Cancer nanomedicine combined with immunotherapy has become a promising strategy for treating cancer in terms of safety and potency; however, precise regulation of the activation of antitumor immunity remains challenging. We herein report a smart semiconducting polymer nano-immunomodulator (SPNI) in response to acidic tumor microenvironment (TME) for precision photodynamic immunotherapy of cancer. SPNI is self-assembled by a NIR-absorbing semiconducting polymer, and an amphipathic polymer conjugated with a Toll like receptor 7 (TLR7) agonist via an acid-liable linker. Upon arrival at tumor site, SPNI undergoes hydrolysis and triggers an efficient liberation of TLR7 agonist in response to acidic TME for DC activation. Moreover, SPNI exerts photodynamic effects for direct tumor eradication and immunogenic cancer cell death under NIR photoirradiation. The synergistic action of released immunogenic factors and acidic TME-activated TLR7 agonist can serve as an in situ generated cancer vaccine to evoke strong antitumor activities. Notably, such localized immune activation boosts systemic antitumor immune responses, resulting in enhanced cytotoxic CD8+ T infiltration to inhibit tumor growth and metastasis. Thereby, this work presents a general strategy to devise prodrug of immunotherapeutics for precise regulation of cancer immunotherapy. This article is protected by copyright. All rights reserved.
    Keywords:  Organic nanoparticles; immunotherapy; photodynamic therapy; precision nanomedicine
  3. ACS Nano. 2021 Dec 03.
      Gut microbiota dynamically participate in diverse physiological activities with direct impact on the host's health. A range of factors associated with the highly complex intestinal flora ecosystem poses challenges in regulating the homeostasis of microbiota. The consumption of live probiotic bacteria, in principle, can address these challenges and confer health benefits. In this context, one of the major problems is ensuring the survival of probiotic cells when faced with physical and chemical assaults during their intake and subsequent gastrointestinal passage to the gut. Advances in the field have focused on improving conventional encapsulation techniques in the microscale to achieve high cell viability, gastric and temperature resistance, and longer shelf lives. However, these microencapsulation approaches are known to have limitations with possible difficulties in clinical translation. In this Perspective, we present a brief overview of the current progress of different probiotic encapsulation methods and highlight the contemporary and emerging single-cell encapsulation strategies using nanocoatings for individual probiotic cells. Finally, we discuss the relative advantages of various nanoencapsulation approaches and the future trend toward developing coated probiotics with advanced features and health benefits.
  4. Mater Horiz. 2021 Aug 01. 8(8): 2251-2259
      RNA drugs hold real potential for tackling devastating diseases that are currently resistant to small molecule drugs or monoclonal antibodies. However, since these drugs are unstable in vivo and unable to pass through cellular membranes their clinical realization is limited by their successful delivery to target sites. Herein we report on the design of a combinatorial library of polyester lipomers based on the renewable monomer, ε-decalactone (ε-DL), via organocatalytic ring-opening polymerization for mRNA delivery. The ε-DL lipomers showed a surprisingly efficient ability to target the lungs upon intravenous administration. Interestingly, most of the lipomers achieved functional EGFP expression in the lungs, while minimally transfecting hepatocytes and splenic cells. This simple approach for the design of biodegradable materials has the potential for the clinical translation of genetic medicines for the treatment of lung diseases.
  5. Small. 2021 Dec 02. e2106281
      DNA-based nanoprobes integrated with various imaging signals have been employed for fabricating versatile biosensor platforms for the study of intracellular biological process and biomarker detection. The nanoprobes developments also provide opportunities for endogenous microRNA (miRNA) in situ analysis. In this review, the authors are primarily interested in various DNA-based nanoprobes for miRNA biosensors and declare strategies to reveal how to customize the desired nanoplatforms. Initially, various delivery vehicles for nanoprobe architectures transmembrane transport are delineated, and their biosecurity and ability for resisting the complex cellular environment are evaluated. Then, the novel strategies for designing DNA sequences as target miRNA specific recognition and signal amplification modules for miRNA detection are presented. Afterward, recent advances in imaging technologies to accurately respond and produce significant signal output are summarized. Finally, the challenges and future directions in the field are discussed.
    Keywords:  DNA-based nanoprobes; biosensors; delivery vehicles; in situ detection; microRNA imaging
  6. Nanoscale. 2021 Dec 03.
      Lymphocytes play a vital role in immunosurveillance through sensing biomolecules and eliminating targeted invaders. Compared with conventional therapies that depend on drug loading, lymphocytes are advantageous as they are able to ensure self-regulated therapeutics. Here, novel multi-compartmental DNA hydrogel particles were synthesized using a microfluidic assembly for intelligent cancer treatment via the logic-based control of siRNA release without external stimulation. The sensing sequence (D1) was compartmentalized from the treatment sequence (D2) with the use of core-shell DNA hydrogel particles. When D1 detects a cancer-associated biomarker, miRNA-21, a sequence cascade is triggered to release siRNA from D2, effectively eliminating the targeted cancer cells via lymphocyte-inspired precision medicine.
  7. ACS Nano. 2021 Dec 03.
      Development of innovative nanomedicine formulations to traverse the blood-brain barrier (BBB) for effective theranostics of glioma remains a great challenge. Herein, we report the creation of macrophage membrane-camouflaged multifunctional polymer nanogels coloaded with manganese dioxide (MnO2) and cisplatin for magnetic resonance (MR) imaging-guided chemotherapy/chemodynamic therapy (CDT) of orthotopic glioma. Redox-responsive poly(N-vinylcaprolactam) (PVCL) nanogels (NGs) formed via precipitation polymerization were in situ loaded with MnO2 and physically encapsulated with cisplatin to have a mean size of 106.3 nm and coated with macrophage membranes to have a good colloidal stability. The generated hybrid NGs display dual pH- and redox-responsive cisplatin and Mn(II) release profiles and can deplete glutathione (GSH) rich in tumor microenvironment through reaction with disulfide-containing cross-linkers within the NGs and MnO2. The thus created Mn(II) enables enhanced CDT through a Fenton-like reaction and T1-weighted MR imaging, while the loaded cisplatin not only exerts its chemotherapy effect but also promotes the reactive oxygen species generation to enhance the CDT efficacy. Importantly, the macrophage membrane coating rendered the hybrid NGs with prolonged blood circulation time and ability to traverse BBB for specific targeted chemotherapy/CDT of orthotopic glioma. Our study demonstrates a promising self-adaptive and cooperative NG-based nanomedicine platform for highly efficient theranostics of glioma, which may be extended to tackle other difficult cancer types.
    Keywords:  PVCL nanogels; blood−brain barrier; chemotherapy; enhanced chemodynamic therapy; macrophage membrane; manganese dioxide
  8. Adv Mater. 2021 Nov 28. e2108348
      Early diagnosis of acute liver failure (ALF) is critical for a curable treatment of the patients, because most existing ALF therapies have narrow therapeutic time windows after disease onset. Reactive oxygen species (ROS), which lead to the sequential occurrences of hepatocyte necrosis and the leakage of alanine aminotransferase (ALT), represent early biomarkers of ALF. Photoacoustic imaging is emerging as a powerful tool for in vivo imaging of ROS. However, high-performance imaging probes that can boost the photoacoustic signals of short-lived ROS of ALF are yet to be developed, and there remains a great challenge for ROS-based imaging of ALF. Herein, we present a ROS-sensitive nanozyme-augmented photoacoustic nanoprobe for successful in vivo imaging of ALF. The deep-penetrated photoacoustic signals of nanoprobe can be activated by the overexpressed ROS in ALF due to the synergy between nanocatalytic bubbles generation and thermoelastic expansion. Impressively, the nanozyme-augmented ROS imaging enables earlier diagnosis of ALF than clinical ALT method, and the ROS-activated catalytic activity of nanoprobe permits timely nanocatalytic therapy of ALF. This article is protected by copyright. All rights reserved.
    Keywords:  Acute liver failure; ceria nanozyme; early diagnosis; photoacoustic imaging
  9. Angew Chem Int Ed Engl. 2021 Dec 01.
      Mitochondrial function in cells declines with aging and with neurodegeneration, due in large part to accumulated mutations in mitochondrial DNA (mtDNA) that arise from deficient DNA repair. However, measuring this repair activity is challenging. Here we employ a molecular approach for visualizing mitochondrial base excision repair (BER) activity in situ by use of a fluorescent probe ( UBER ) that reacts rapidly with AP sites resulting from BER activity. Administering the probe to cultured cells revealed signals that were localized to mitochondria, enabling selective observation of mtDNA BER intermediates. The probe showed elevated DNA repair activity under oxidative stress, and responded to suppression of glycosylase activity. Furthermore, the probe illuminated the time lag between the initiation of oxidative stress and the initial step of BER. Absence of MTH1 in cells resulted in elevated demand for BER activity upon extended oxidative stress, while the absence of OGG1 activity limited glycosylation capacity.
    Keywords:  DNA damage and repair; dynamics; fluorescence probes; mitochondrial DNA
  10. Cancer Biol Med. 2021 Dec 01. pii: j.issn.2095-3941.2021.0294. [Epub ahead of print]
      MicroRNAs (miRNAs) are a class of endogenously expressed non-coding regulators of the genome with an ability to mediate a variety of biological and pathological processes. There is growing evidence demonstrating frequent dysregulation of microRNAs in cancer cells, which is associated with tumor initiation, development, migration, invasion, resisting cell death, and drug resistance. Studies have shown that modulation of these small RNAs is a novel and promising therapeutic tool in the treatment of a variety of diseases, especially cancer, due to their broad influence on multiple cellular processes. However, suboptimal delivery of the appropriate miRNA to the cancer sites, quick degradation by nucleases in the blood circulation, and off target effects have limited their research and clinical applications. Therefore, there is a pressing need to improve the therapeutic efficacy of miRNA modulators, while at the same time reducing their toxicities. Several delivery vehicles for miRNA modulators have been shown to be effective in vitro and in vivo. In this review, we will discuss the role and importance of miRNAs in cancer and provide perspectives on currently available carriers for miRNA modulation. We will also summarize the challenges and prospects for the clinical translation of miRNA-based therapeutic strategies.
    Keywords:  MiRNAs; cancer therapy; clinical translation; delivery systems; dysregulation
  11. Adv Mater. 2021 Nov 30. e2107924
      The visionary idea that RNA adopts non-biological roles in today's nanomaterial world has been nothing short of phenomenal. These RNA molecules have ample chemical functionality and self-assemble to form distinct nanostructures in response to external stimuli. They may be combined with inorganic materials to produce nanomachines that carry cargo to the target sites in a controlled manner and respond dynamically to environmental changes. Comparable to biological cells, programmed RNA nanomachines have the potential to replicate bone healing in vitro. Here, an RNA-biomineral nanomachine has been developed that accomplishes intrafibrillar and extrafibrillar mineralization of collagen scaffolds to mimic bone formation in vitro. Molecular dynamics simulation indicates that noncovalent hydrogen bonding provides the energy source that initiates self-assembly of these RNA-biomineral nanomachines. Incorporation of RNA-biomineral nanomachines into collagen scaffolds in vivo creates an osteoinductive microenvironment within a bone defect that is conducive to rapid biomineralization and osteogenesis. Addition of RNA degrading enzymes into the RNA-biomineral nanomachines further creates a stop signal that inhibits unwarranted bone formation in tissues other than bone and teeth. The potential of RNA in building functional nanostructures has been underestimated in the past. The concept of RNA-biomineral nanomachines participating in physiological processes may transform the nanoscopic world of life science. This article is protected by copyright. All rights reserved.
    Keywords:  RNA; amorphous calcium phosphate; biomineralization; bone healing; nanomachine
  12. Nat Commun. 2021 Dec 01. 12(1): 7003
      Cancer cells acquire genetic heterogeneity to escape from immune surveillance during tumor evolution, but a systematic approach to distinguish driver from passenger mutations is lacking. Here we investigate the impact of different immune pressure on tumor clonal dynamics and immune evasion mechanism, by combining massive parallel sequencing of immune edited tumors and CRISPR library screens in syngeneic mouse tumor model and co-culture system. We find that the core microRNA (miRNA) biogenesis and targeting machinery maintains the sensitivity of cancer cells to PD-1-independent T cell-mediated cytotoxicity. Genetic inactivation of the machinery or re-introduction of ANKRD52 frequent patient mutations dampens the JAK-STAT-interferon-γ signaling and antigen presentation in cancer cells, largely by abolishing miR-155-targeted silencing of suppressor of cytokine signaling 1 (SOCS1). Expression of each miRNA machinery component strongly correlates with intratumoral T cell infiltration in nearly all human cancer types. Our data indicate that the evolutionarily conserved miRNA pathway can be exploited by cancer cells to escape from T cell-mediated elimination and immunotherapy.