bims-drudre Biomed News
on Targeted drug delivery and programmed release mechanisms
Issue of 2022‒02‒20
thirteen papers selected by
Ceren Kimna
Technical University of Munich

  1. Adv Mater. 2022 Feb 17. e2109581
      Current advances in materials science have demonstrated that extracellular mechanical cues can define cell function and cell fate. However, a fundamental understanding of the manner in which intracellular mechanical cues affect cell mechanics remain elusive. We here describe how intracellular mechanical hindrance, reinforcement and supports interfere with the cell cycle and promote cell death. Reproducible devices with highly controlled size, shape and with a broad range of stiffness were internalized in HeLa cells. Once inside, they induced characteristic cell cycle deviations and promoted cell death. Device shape and stiffness were the dominant determinants of mechanical impairment. Device structural support to the cell membrane and centring during mitosis maximized their effects, preventing spindle centring and correct chromosome alignment. Nanodevices reveal that the spindle generated forces larger than 114 nN which overcome intracellular confinement by relocating the device to a less damaging position. By using intracellular mechanical drugs, this work provides a foundation to defining the role of intracellular constrains on cell function and fate, with relevance to fundamental cell mechanics and nanomedicine. This article is protected by copyright. All rights reserved.
    Keywords:  biomaterials; cell cycle; mechanobiology; nanomaterials; nanomedicine; silicon chips
  2. Small. 2022 Feb 12. e2107461
      Tumor antigens released from tumor cells after local photothermal therapy (PTT) can activate the tumor-specific immune responses, which are critical for eliminating the residual lesions and distant metastases. However, the limited recognition efficiency of released tumor antigens by the immune system and the immunosuppressive microenvironment lead to ineffective antitumor immunity. Here, an in situ multifunctional vaccine based on bacterial outer membrane vesicles (OMVs, 1-MT@OMV-Mal) is developed by surface conjunction of maleimide groups (Mal) and interior loading with inhibitor of indoleamine 2, 3-dioxygenase (IDO), 1-methyl-tryptophan (1-MT). 1-MT@OMV-Mal can bind to the released tumor antigens after PTT, and be efficiently recognized and taken up by dendritic cells. Furthermore, in situ injection of 1-MT@OMV-Mal simultaneously overcomes the immune inhibition of IDO on tumor-infiltrating effector T cells, leading to remarkable inhibition on both primary and distant tumors. Together, a promising in situ vaccine based on OMVs to facilitate immune-mediated tumor clearance after PTT through orchestrating antigen capture and immune modulation is presented.
    Keywords:  antigen capture; in situ vaccines; indoleamine 2,3-dioxygenase; photothermal therapies
  3. Adv Mater. 2022 Feb 15. e2110219
      Tumorigenic environments, especially aberrantly over-expressed oncogenic microRNAs, play critical role in various activities of tumor progression. However, developing strategies to effectively utilize and manipulate these oncogenic microRNAs for tumor therapy is still a challenge. To address this challenge, we have fabricated spherical nucleic acids (SNAs) consisting of gold nanoparticles in the core and antisense oligonucleotides as the shell. Hybridized to the oligonucleotide shell was a DNA sequence to which doxorubicin was conjugated (DNA-DOX). The oligonucleotides shell was designed to capture over-expressed miR-21/miR-155 and inhibit the expression of these oncogenic miRNAs in tumor cells after tumor accumulation to manipulate genetic environment for accurate gene therapy. This process would further induce the aggregation of these SNAs, which not only generated photothermal agents to achieve on-demand photothermal therapy in situ, but enlarged the size of SNAs to enhance the retention time in tumor for sustained therapy. The capturing of the relevant miRNAs simultaneously triggered the intracellular release of the DNA-DOX from the SNAs to deliver tumor-specific chemotherapy. Both in vivo and in vitro results indicated that this combination strategy has excellent tumor inhibition properties with high survival rate of tumor-bearing mice, which could be a promising candidate for effective tumor treatment. This article is protected by copyright. All rights reserved.
    Keywords:  Capture and Inhibition of Oncogenic MicroRNAs (miR-155/miR-21); Intelligent Gold Nanoparticles; Utilization and Manipulation of Tumorigenic Environments; miR-155 Triggered Chemotherapy; miR-21 Dependent Photothermal Therapy
  4. Angew Chem Int Ed Engl. 2022 Feb 18.
      Intravesical administration of first-line drugs has shown failure in the treatment of bladder cancer owing to poor tumor retention time of chemotherapeutics. Herein, we report an intracellular hydrolytic condensation ( IHC ) system to in situ construct long-term retentive nano-drug depots, wherein sustained drug release results in highly efficient suppression of bladder cancer. Briefly, the designed doxorubicin (Dox)-silane conjugates self-assemble into silane-based prodrug nanoparticles, which condense into silicon particle-based nano-drug depots inside tumor cells. Significantly, we demonstrate that the IHC system possesses highly potent antitumor efficacy, which leads to the regression and eradication of large established tumors and simultaneously extends the overall survival of air pouch bladder cancer mice compared with that of mice treated with Dox. The concept of intracellular hydrolytic condensation can be extended via conjugating other chemotherapeutic drugs, which may facilitate rational design of novel nanomedicines for augmentation of chemotherapy.
    Keywords:  self-assembly, chemotherapy, bladder cancer, sustained release, nano-drug depots
  5. Adv Mater. 2022 Feb 17. e2110062
      Melanoma is the most lethal malignancy in skin cancer and may occur at any site and express melanocytes. Due to malignant melanoma's invasion and migration nature, conventional therapies make it challenging to remove the whole tumor tissue while undertaking the high risks of tumor recurrence. Regarding the emerging targeted therapies and immunotherapy, drug resistance and low immunotherapeutic activity remain significant challenges. It is thus becoming urgently important to develop alternative strategies for melanoma therapy. Herein, we develop a novel bifunctional protein-based photo-thermal bioplaster (PPTB) for non-invasive tumor therapy and skin tissue regeneration. The complexation of adhesive protein and gold nanorods (GNRs) endow the obtained PPTB with good biocompatibility, controllable near-infrared (NIR) light-mediated adhesion performance, and high photo-thermal performance. Therefore, the PPTB bioagent facilitates skin adhesion and effectively transfers heat from skin to tumor. This behavior endows PPTB capability to eradicate skin tumors conveniently. Thus, our assembly strategy enables this hybrid bioplaster to hold great potential for skin-related tumor treatment. This article is protected by copyright. All rights reserved.
    Keywords:  adhesive protein; bioplaster; gold nanoparticle; photo-thermal effect; skin cancer therapy
  6. Nat Commun. 2022 Feb 17. 13(1): 912
      To program intercellular communication for biomedicine, it is crucial to regulate the secretion and surface display of signaling proteins. If such regulations are at the protein level, there are additional advantages, including compact delivery and direct interactions with endogenous signaling pathways. Here we create a modular, generalizable design called Retained Endoplasmic Cleavable Secretion (RELEASE), with engineered proteins retained in the endoplasmic reticulum and displayed/secreted in response to specific proteases. The design allows functional regulation of multiple synthetic and natural proteins by synthetic protease circuits to realize diverse signal processing capabilities, including logic operation and threshold tuning. By linking RELEASE to additional sensing and processing circuits, we can achieve elevated protein secretion in response to "undruggable" oncogene KRAS mutants. RELEASE should enable the local, programmable delivery of intercellular cues for a broad variety of fields such as neurobiology, cancer immunotherapy and cell transplantation.
  7. Small. 2022 Feb 19. e2107534
      Alzheimer disease (AD) is the leading cause of dementia that affects millions of old people. Despite significant advances in the understanding of AD pathobiology, no disease modifying treatment is available. MicroRNA-124 (miR-124) is the most abundant miRNA in the normal brain with great potency to ameliorate AD-like pathology, while it is deficient in AD brain. Herein, the authors develop a DNA nanoflowers (DFs)-based delivery system to realize exogenous supplementation of miR-124 for AD therapy. The DFs with well-controlled size and morphology are prepared, and a miR-124 chimera is attached via hybridization. The DFs are further modified with RVG29 peptide to simultaneously realize brain-blood barrier (BBB) penetration and neuron targeting. Meanwhile, Rutin, a small molecular ancillary drug, is co-loaded into the DFs structure via its intercalation into the double stranded DNA region. Interestingly, Rutin could synergize miR-124 to suppress the expression of both BACE1 and APP, thus achieving a robust inhibition of amyloid β generation. The nanosystem could pro-long miR-124 circulation in vivo, promote its BBB penetration and neuron targeting, resulting in a significant increase of miR-124 in the hippocampus of APP/PS1 mice and robust therapeutic efficacy in vivo. Such a bio-derived therapeutic system shows promise as a biocompatible nanomedicine for AD therapy.
    Keywords:  RVG29; blood-brain barrier; microRNAs; nanoparticles; neurodegenerative diseases; β-amyloid
  8. Proc Natl Acad Sci U S A. 2022 Feb 22. pii: e2116271119. [Epub ahead of print]119(8):
      Safe and efficacious systemic delivery of messenger RNA (mRNA) to specific organs and cells in vivo remains the major challenge in the development of mRNA-based therapeutics. Targeting of systemically administered lipid nanoparticles (LNPs) coformulated with mRNA has largely been confined to the liver and spleen. Using a library screening approach, we identified that N-series LNPs (containing an amide bond in the tail) are capable of selectively delivering mRNA to the mouse lung, in contrast to our previous discovery that O-series LNPs (containing an ester bond in the tail) that tend to deliver mRNA to the liver. We analyzed the protein corona on the liver- and lung-targeted LNPs using liquid chromatography-mass spectrometry and identified a group of unique plasma proteins specifically absorbed onto the surface that may contribute to the targetability of these LNPs. Different pulmonary cell types can also be targeted by simply tuning the headgroup structure of N-series LNPs. Importantly, we demonstrate here the success of LNP-based RNA therapy in a preclinical model of lymphangioleiomyomatosis (LAM), a destructive lung disease caused by loss-of-function mutations in the Tsc2 gene. Our lung-targeting LNP exhibited highly efficient delivery of the mouse tuberous sclerosis complex 2 (Tsc2) mRNA for the restoration of TSC2 tumor suppressor in tumor and achieved remarkable therapeutic effect in reducing tumor burden. This research establishes mRNA LNPs as a promising therapeutic intervention for the treatment of LAM.
    Keywords:  lipid nanoparticles; lung-targeted delivery; lymphangioleiomyomatosis; mRNA; tuberous sclerosis complex
  9. Adv Healthc Mater. 2022 Feb 19. e2102685
      Blood clotting disorders such as pulmonary embolism is associated with high morbidity and mortality. A large portion of thrombotic events occurs post-operative and after hospital discharge. Therefore, easily applicable, non-invasive and long-term monitoring of thrombosis occurrence is critical for urgent clinical intervention. Here, we propose the use of ionic liquids as a skin transport facilitator to deliver thrombin-sensitive nanosensors that enable prolonged monitoring of pulmonary embolism. Co-formulation of nanosensors with choline and geranic acid (CAGE) ionic liquids demonstrated significant transdermal diffusion into the dermis of the skin and provided sustained release into the blood throughout 72 hours. Upon reaching the systemic circulation, the nanosensors released reporter molecules into the urine by responding to activation of the clotting cascade and retained a diagnostic power for 24 hours in an acute pulmonary embolism mouse model. These results demonstrate a proof-of-concept disease monitoring system that can be topically applied by patients and potentially reducing mortality and high cost of hospitalization. This article is protected by copyright. All rights reserved.
    Keywords:  activity-based nanosensor; drug delivery; ionic liquid; nanoparticles; protease; thrombosis; transdermal delivery
  10. Adv Mater. 2022 Feb 17. e2109969
      The rapid evolution of cell-based theranostics has attracted extensive attention due to their unique advantages in biomedical applications. However, only the inherent functions of cells cannot meet the needs of malignant tumor treatment. Thus endowing original cells with new characteristics to generate multifunctional living cells may hold a tremendous promise. Here, for the first time, we used the nanoengineering method to combine customized liposomes with neutrophils, generating oxygen-carrying sonosensitizer cells with acoustic functions, which we called Acouscyte/O2 , for the visual diagnosis and treatment of cancer. Specifically, oxygen-carried perfluorocarbon and temoporfin were encapsulated into cRGD peptide modified multilayer liposomes (C-ML/HPT/O2 ), which were then loaded into live neutrophils to obtain Acouscyte/O2 . Acouscyte/O2 could not only carry a large amount of oxygen but also exhibit the ability of long circulation, inflammation triggered recruitment and decomposition. Importantly, Acouscyte/O2 could be selectively accumulated in tumors, effectively enhanced tumor oxygen levels, and triggered anticancer sonodynamics in response to ultrasound stimulation, leading to completely obliterating tumors and efficiently extending survival time of tumor-bearing mice with minimal systemic adverse effects. Meanwhile, the tumors could be real-time monitored by temoporfin-mediated fluorescence imaging and PFC-microbubble enhanced ultrasound imaging. Therefore, the nanoengineered neutrophils, i.e., Acouscyte/O2 , were a new type of multifunctional cellular drug, which provides a new platform for the diagnosis and sonodynamic therapy of solid malignant tumors. This article is protected by copyright. All rights reserved.
    Keywords:  malignant tumors; multimode imaging; nanoengineered neutrophils; sonodynamic therapy; sonosensitizer
  11. Nat Chem Biol. 2022 Feb 17.
      Cell-free biosensors are powerful platforms for monitoring human and environmental health. Here, we expand their capabilities by interfacing them with toehold-mediated strand displacement circuits, a dynamic DNA nanotechnology that enables molecular computation through programmable interactions between nucleic acid strands. We develop design rules for interfacing a small molecule sensing platform called ROSALIND with toehold-mediated strand displacement to construct hybrid RNA-DNA circuits that allow fine-tuning of reaction kinetics. We use these design rules to build 12 different circuits that implement a range of logic functions (NOT, OR, AND, IMPLY, NOR, NIMPLY, NAND). Finally, we demonstrate a circuit that acts like an analog-to-digital converter to create a series of binary outputs that encode the concentration range of the molecule being detected. We believe this work establishes a pathway to create 'smart' diagnostics that use molecular computations to enhance the speed and utility of biosensors.
  12. ACS Appl Mater Interfaces. 2022 Feb 17.
      Cancer-associated fibroblasts (CAFs), an important type of stromal cells in the tumor microenvironment (TME), are responsible for creating physical barriers to drug delivery and penetration in tumor tissues. Thus, effectively downregulating CAFs to destroy the physical barrier may allow enhanced penetration and accumulation of therapeutic drugs, thereby improving therapeutic outcomes. Herein, a matrix metalloproteinase (MMP)-triggered dual-targeting hybrid micelle-in-liposome system (RPM@NLQ) was constructed to sequentially deliver quercetin (Que) and paclitaxel (PTX) for fibrotic TME remodeling and chemotherapy potentiation. Specifically, antifibrotic Que and small-sized RGD-modified micelles containing PTX (RPM) were co-encapsulated into MMP-sensitive liposomes, and the liposomes were further adorned with the NGR peptide (NL) as the targeting moiety. The resulting RPM@NLQ first specifically accumulated at the tumor site under the guidance of the NGR peptide after intravenous administration and then released Que and RPM in response to the extensive expression of MMP in the TME. Subsequently, Que was retained in the stroma to remarkably downregulate fibrosis and decrease the stromal barrier by downregulating Wnt16 expression in CAFs, which further resulted in a significant increase of RPM for deeper tumor. Thus, RPM could precisely target and kill breast cancer cells locally. Consequently, prolonged blood circulation, selective cascade targeting of tumor tissue and tumor cells, enhanced penetration, and excellent antitumor efficacy have been demonstrated in vitro and in vivo. In conclusion, as-designed sequential delivery systems for fibrotic TME remodeling and chemotherapy potentiation may provide a promising adjuvant therapeutic strategy for breast and other CAF-rich tumors.
    Keywords:  MMP-sensitive; cancer-associated fibroblasts; dual-targeting; hybrid micelle-in-liposome system; sequential delivery of quercetin and paclitaxel
  13. Cells. 2022 Jan 28. pii: 452. [Epub ahead of print]11(3):
      Within the past years, more and more attention has been devoted to the epigenetic dysregulation that provides an additional window for understanding the possible mechanisms involved in the pathogenesis of autoimmune rheumatic diseases. Rheumatoid arthritis (RA) is a heterogeneous disease where a specific immunologic and genetic/epigenetic background is responsible for disease manifestations and course. In this field, microRNAs (miRNA; miR) are being identified as key regulators of immune cell development and function. The identification of disease-associated miRNAs will introduce us to the post-genomic era, providing the real probability of manipulating the genetic impact of autoimmune diseases. Thereby, different miRNAs may be good candidates for biomarkers in disease diagnosis, prognosis, treatment and other clinical applications. Here, we outline not only the role of miRNAs in immune and inflammatory responses in RA, but also present miRNAs as diagnostic/prognostic biomarkers. Research into miRNAs is still in its infancy; however, investigation into these novel biomarkers could progress the use of personalized medicine in RA treatment. Finally, we discussed the possibility of miRNA-based therapy in RA patients, which holds promise, given major advances in the therapy of patients with inflammatory arthritis.
    Keywords:  autoimmune disease; bone destruction; immune and inflammatory responses; microRNA; rheumatoid arthritis (RA); synovial hyperplasia