bims-drudre Biomed News
on Targeted drug delivery and programmed release mechanisms
Issue of 2022‒03‒13
sixteen papers selected by
Ceren Kimna
Technical University of Munich

  1. Small. 2022 Mar 11. e2107354
      Small extracellular vesicles (sEVs) secreted by mesenchymal stem cells (MSCs) have been extensively studied in recent years. sEV contents change with the secreting cell state. When MSCs are exposed to an inflammatory environment, they release more functional growth factors, exosomes, and chemokines. Herein, MSCs are stimulated to alter sEV cargos and functions to regulate the inflammatory microenvironment and promote tissue regeneration. Sequencing of sEV miRNAs shows that certain RNAs conducive to cell function are upregulated. In this study, in vitro cell function experiments show that both inflammation-stimulated adipose-derived MSC (ADSC)-derived sEV (IAE) and normal ADSC-derived sEV (AE) promote cell proliferation; IAE also significantly improves cell migration. Regarding macrophage polarization regulation, IAE significantly promotes M2 macrophage differentiation. RNA-sequencing analysis indicates that high miR-27b-3p expression levels in IAE may regulate macrophages by targeting macrophage colony-stimulating factor-1 (CSF-1). In vivo, a rabbit temporomandibular joint (TMJ) condylar osteochondral defect model shows that both AE and IAE promote TMJ regeneration, with IAE having the most significant therapeutic effect. Therefore, the authors confirm that exposing MSCs to an inflammatory environment can feasibly enhance sEV functions and that modified sEVs achieve better therapeutic effects.
    Keywords:  extracellular vesicles; inflammation; miR-27b-3p; regeneration; temporomandibular joint
  2. Small. 2022 Mar 09. e2200115
      Radiotherapy and chemotherapy are limited by insufficient therapeutic efficacy of low-dose radiation and nonspecific drug biodistribution. Herein, an acid-responsive aggregated nanosystem (AuNPs-D-P-DA) loaded with doxorubicin (DOX) is designed for radiosensitization and synergistic chemoradiotherapy. In response to the acid microenvironment of esophageal cancer (EC), small-sized AuNPs-D-P-DA forms large-sized gold nanoparticle (AuNPs) aggregates in tumor tissues to hinder the backflow of AuNPs to the circulation, resulting in enhanced tumor accumulation and retention. Simultaneously, the AuNPs-based radiosensitization is significantly improved because of the high concentration and large size of intratumoral AuNPs, while DOX are delivered and released specifically into tumor cells triggered by the acid microenvironment for chemo-radio synergistic therapy. Acid-responsive AuNPs exacerbate radiation-induced DNA damage, cell apoptosis, cell cycle arrest, and low colony formation ability in vitro and enhance anti-tumor efficacy in vivo compared to un-responsive control. When combined with acid-responsive DOX, the therapeutic efficacy of the formulation is further improved by their synergistic effect. After the treatment of acid-responsive AuNPs plus radiotherapy, fatty acid metabolism is reprogrammed in xenograft models, which provides potential targets for further improvement of radiosensitization. In summary, the acid-responsive AuNPs-D-P-DA nanosystem leverages the radio- and chemotherapeutic synergies of AuNPs-sensitized X-ray irradiation and acid-responsive DOX in the treatment of EC.
    Keywords:  DNA damage; acid-responsive aggregation; chemoradiotherapy; fatty acid metabolism; radiosensitization
  3. Nat Rev Mater. 2022 Feb 28. 1-18
      Inflammation plays an important role in the response to danger signals arising from damage to our body and in restoring homeostasis. Dysregulated inflammatory responses occur in many diseases, including cancer, sepsis and autoimmunity. The efficacy of anti-inflammatory drugs, developed for the treatment of dysregulated inflammation, can be potentiated using biomaterials, by improving the bioavailability of drugs and by reducing side effects. In this Review, we first outline key elements and stages of the inflammatory environment and then discuss the design of biomaterials for different anti-inflammatory therapeutic strategies. Biomaterials can be engineered to scavenge danger signals, such as reactive oxygen and nitrogen species and cell-free DNA, in the early stages of inflammation. Materials can also be designed to prevent adhesive interactions of leukocytes and endothelial cells that initiate inflammatory responses. Furthermore, nanoscale platforms can deliver anti-inflammatory agents to inflammation sites. We conclude by discussing the challenges and opportunities for biomaterial innovations in addressing inflammation.
    Keywords:  Biomedical materials
  4. J Am Chem Soc. 2022 Mar 07.
      Constructing artificial dynamic architectures inside cells to rationally interfere with organelles is emerging as an efficient strategy to regulate the behaviors and fate of cells, thus providing new routes for therapeutics. Herein, we develop an intracellular K+-mediating dynamic assembly of DNA tetrahedrons inside cells, which realizes efficient mitochondrial interference and consequent regulation on the energy metabolism of living cells. In the designer DNA tetrahedron, one vertex was modified with triphenylphosphine (TPP) for mitochondrial targeting, and the other three vertexes were tethered with guanine-rich sequences that could realize K+-mediating formation of intermolecular G-quadruplexes, which consequently led to the assembly of DNA tetrahedrons to form aggregates in the cytoplasm. The DNA aggregates specially targeted mitochondria and served as a polyanionic barrier for substance communication, thus generating a significant inhibition effect on the aerobic respiration function of mitochondria and the associated glycolysis process, which consequently reduced the production of intracellular adenosine triphosphate (ATP). The lack of ATP impeded the formation of lamellipodium that was essential for the movement of cells, consequently resulting in a significant inhibitory effect on cell migration. Remarkably, the migration capacity was suppressed by as high as 50% for cancer cells. This work provides a new strategy for the manipulation of organelles via the endogenous molecule-mediating dynamic assembly of exogenous artificial architectures inside living cells, which is envisioned to have great potential in precise biomedicine.
  5. Small. 2022 Mar 09. e2107757
      In the research of cancer cell invasion and metastasis, recreation of physiologically relevant and faithful three-dimensional (3D) tumor models that recapitulate spatial architecture, spatiotemporal control of cell communication and signaling pathways, and integration of extracellular cues remains an open challenge. Here, a programmable multifunctional 3D cancer cell invasion microbuckets-hydrogel (Mb-H) platform is developed by integrating various function-variable microbuckets and extracellular matrix (ECM)-like hydrogels. Based on this Mb-H micro platform, the aggregation of multi-cancer cells is well controlled to form cancer cell spheroids, and the guiding relationship of single-cell migration and collective cell migration during the epithelial-mesenchymal transition (EMT) of cancer cell invasion are demonstrated. By programming and precisely assembling multiple functions in one system, the Mb-H platform with spatial-temporal controlled release of cytokine transforming growth factor beta (TGF-β) and various functionalized Mb-H platforms with intelligent adjustment of cell-matrix interactions are engineered to coordinate the 3D invasive migration of cancer cell spheroids. This programmable and adaptable 3D cancer cell invasion micro platform takes a new step toward mimicking the dynamically changing (localized) tumor microenvironment and exhibits wide potential applications in cancer research, bio-fabrication, cell signaling, and drug screening.
    Keywords:  3D cancer cell invasion; directional cancer cell migration; dynamic TGF-β release; hydrogels; programmable multiple functions
  6. Sci Adv. 2022 Mar 11. 8(10): eabh1419
      The short half-life in the GI tract necessitates an excess of drugs causing side effects of oral formulations. Here, we report the development and deployment of Bacterioboat, which consists of surface-encapsulated mesoporous nanoparticles on metabolically active Lactobacillus reuteri as a drug carrier suitable for oral administration. Bacterioboat showed up to 16% drug loading of its dry weight, intestinal anchorage around alveoli regions, sustained release, and stability in physiological conditions up to 24 hours. In vivo studies showed that oral delivery of 5-fluorouracil leads to increased potency, resulting in improved shrinkage of solid tumors, enhanced life expectancy, and reduced side effects. This novel design and development make this system ideal for orally administrable drugs with low solubility or permeability or both and even making them effective at a lower dose.
  7. Adv Sci (Weinh). 2022 Mar 11. e2105807
      Due to the complexity, aggressiveness, and heterogeneity of malignant melanoma, it is difficult to eradicate the whole tumor through conventional treatment. Herein, a strategy of metabolic engineering labeled anaerobic oncolytic bacteria (Clostridium butyricum) is demonstrated to achieve the ablation of melanoma. In this system, the metabolic substrate of C. butyricum d-alanine (d-Ala) is first conjugated with a photosensitizer (TPApy) showing aggregation-induced emission (AIE). The yielded metabolic substrate of d-Ala-TPAPy can be metabolically incorporated into bacterial peptidoglycan to form engineered C. Butyricum. Once the engineered C. butyricum is injected into melanoma, the bacteria can only proliferate in an anaerobic zone, stimulate the tumor immune microenvironment, and ablate the tumor hypoxia region. Following that, the relatively rich oxygen content in the peripheral area can induce the death of C. butyricum. The photosensitizer (PS) on the bacteria can subsequently exert a photodynamic effect in the oxygen-rich region and further remove the melanoma residue under light irradiation. Prominent in vivo melanoma ablation results revealed that the engineering oncolytic bacteria can provide a promising regime for solid tumor eradication.
    Keywords:  Clostridium butyricum; immunotherapy; melanoma; metabolic labeling; photodynamic therapy
  8. J Am Chem Soc. 2022 Mar 07.
      Chemistry is in a powerful position to synthetically replicate biomolecular structures. Adding functional complexity is key to increase the biomimetics' value for science and technology yet is difficult to achieve with poorly controlled building materials. Here, we use defined DNA blocks to rationally design a triggerable synthetic nanopore that integrates multiple functions of biological membrane proteins. Soluble triggers bind via molecular recognition to the nanopore components changing their structure and membrane position, which controls the assembly into a defined channel for efficient transmembrane cargo transport. Using ensemble, single-molecule, and simulation analysis, our activatable pore provides insight into the kinetics and structural dynamics of DNA assembly at the membrane interface. The triggered channel advances functional DNA nanotechnology and synthetic biology and will guide the design of controlled nanodevices for sensing, cell biological research, and drug delivery.
  9. ACS Appl Mater Interfaces. 2022 Mar 08.
      Functionalized biocarriers that can perform bio-orthogonal reactions in tumor cells may provide solutions to overcome the efflux of the chemotherapeutic agent from drug-resistant tumor cells. Herein, we report the enrichment of therapeutic drugs in tumor cells through intracellular click reaction with functionalized bacteria. Specifically, an intracellular bioactive drug enrichment template (OPV@Escherichia coli) is constructed by combining positively charged oligo(phenylene-vinylene)-alkyne (OPV-C≡CH) with E. coli via electrostatic interaction. After the cell uptake of OPV@E. coli and Cu(II)-based complex, Cu(I) generated in situ can catalyze the bio-orthogonal click reaction to covalently anchor the azide-bearing molecules of cyanine 5 (Cy5-N3) and paclitaxel (PTX-N3) on OPV@E. coli. These molecules and their functions were retained and enriched inside the drug-resistant tumor cells A549T, which can label cells with fluorescent probes and selectively induce the apoptosis of drug-resistant tumor cells.
    Keywords:  bacterial template; bio-orthogonal chemistry; drug enrichment; intracellular catalysis; tumor drug resistance
  10. J Am Chem Soc. 2022 Mar 09.
      Viral and synthetic vectors for delivery of nucleic acids impacted genetic nanomedicine by aiding the rapid development of the extraordinarily efficient Covid-19 vaccines. Access to targeted delivery of nucleic acids is expected to expand the field of nanomedicine beyond most expectations. Both viral and synthetic vectors have advantages and disadvantages. The major advantage of the synthetic vectors is their unlimited synthetic capability. The four-component lipid nanoparticles (LNPs) are the leading nonviral vector for mRNA used by Pfizer and Moderna in Covid-19 vaccines. Their synthetic capacity inspired us to develop a one-component multifunctional sequence-defined ionizable amphiphilic Janus dendrimer (IAJD) delivery system for mRNA. The first experiments on IAJDs provided, through a rational-library design combined with orthogonal-modular accelerated synthesis and sequence control in their hydrophilic part, some of the most active synthetic vectors for the delivery of mRNA to lung. The second experiments employed a similar strategy, generating, by a less complex hydrophilic structure, a library of IAJDs targeting spleen, liver, and lung. Here, we report preliminary studies designing the hydrophobic region of IAJDs by using dissimilar alkyl lengths and demonstrate the unexpectedly important role of the primary structure of the hydrophobic part of IAJDs by increasing up to 90.2-fold the activity of targeted delivery of mRNA to spleen, lymph nodes, liver, and lung. The principles of the design strategy reported here and in previous publications indicate that IAJDs could have a profound impact on the future of genetic nanomedicine.
  11. ACS Nano. 2022 Mar 07.
      B-mode ultrasound imaging is a significant anatomic technique in clinic, which can display the anatomic variation in tissues. However, it is difficult to evaluate the functional state of organs and display the physiological information in organisms such as the tumor acidic microenvironment (TME). Herein, inspired by the phenomenon of sonographic acoustic shadow during detecting calculus in clinic, a strategy of self-enhanced acoustic impedance difference is proposed to monitor the acidic TME. BiF3@PDA@PEG (BPP) nanoparticles can self-aggregate in a specific response to the acidic TME to form huge "stones" BiF3@PDA, resulting in an increase of local tumor density, and further causing a significant acoustic impedance difference. In in vitro experiments, the enhanced ultrasound signals change from 15.2 to 196.4 dB, which can discriminate different pH values from 7.0 to 5.0, and the sensitivity can reach to 0.2 value. In in vivo experiments, the enhanced ultrasound signal is 107.7 dB after BPP self-aggregated, displaying the weak acidic TME that has a close relationship with the size and species of the tumor. More importantly, the accuracy is away from the interference of pressure because huge "stones" BiF3@PDA change little. However, SonoVue microbubbles will diffuse and rupture under pressure, which results in false positive signals. To sum up, this strategy will be helpful to the further development of ultrasound molecular imaging.
    Keywords:  BiF3@PDA@PEG nanoparticles; acidic tumor microenvironment; self-enhanced acoustic impedance difference; sonographic acoustic shadow; ultrasound imaging
  12. Science. 2022 Mar 11. 375(6585): 1159-1164
      Intracellular transport is the basis of microscale logistics within cells and is powered by biomolecular motors. Mimicking transport for in vitro applications has been widely studied; however, the inflexibility in track design and control has hindered practical applications. Here, we developed protein-based motors that move on DNA nanotubes by combining a biomolecular motor dynein and DNA binding proteins. The new motors and DNA-based nanoarchitectures enabled us to arrange the binding sites on the track, locally control the direction of movement, and achieve multiplexed cargo transport by different motors. The integration of these technologies realized microscale cargo sorters and integrators that automatically transport molecules as programmed in DNA sequences on a branched DNA nanotube. Our system should provide a versatile, controllable platform for future applications.
  13. ACS Appl Mater Interfaces. 2022 Mar 08.
      Low-abundance biomarker amplification detection systems have been widely used to detect miRNAs; however, "always active" systems are insufficient for high spatial and temporal control of miRNAs. Here, we constructed a light-activated nanodevice (LAN) based on DNA nanotechnology for high spatial and temporal precision detection of low-abundance miRNA. Light-activated hairpin probes and triple-helix molecular switches were modified on the surface of gold nanoparticles (AuNPs) to trigger miRNA on-demand imaging analysis by UV light activation. In the presence of both UV light and miRNA, the LAN releases hairpin DNA and completes the hybridization chain reaction (HCR) with the conformation-altered triple-helix molecular switch, enabling fluorescence imaging of low-abundance miRNAs in living cells. The current work provides an opportunity to develop light-activated signal amplification sensors that can accurately image miRNAs on-demand in both temporal and spatial dimensions.
    Keywords:  gold nanoparticles; light-activated; miRNA; signal amplification; triple-helix
  14. J Control Release. 2022 Mar 07. pii: S0168-3659(22)00118-3. [Epub ahead of print]
      The recent development and prospects of cancer immunotherapy have led to diversification of the types of therapeutic agents used. By simultaneously administering various agents, a more effective therapeutic effect can be expected due to the synergistic effects of multiple therapeutics. In particular, if a substance with adjuvanticity and tumor antigen is delivered at the same time, enhanced cancer immunotherapy can be achieved through high cross-presentation and antigen-presenting cell (APC) maturation. To this end, we developed a polymerized phenylboronic acid (pPBA)-based immunogel for the simultaneous delivery of mannan, which has adjuvanticity and tumor antigen. The immunogel was formed by simple mixing of the polysaccharide mannan with pPBA through the formation of phenylboronic ester between the diol of mannose monomers and phenylboronic acids of pPBA. The immunogel was slowly degraded by hydrolysis to release the loaded tumor antigen. In addition, the released mannan played a key role in both APC maturation in vitro and the upregulation of cross-presentation. Finally, the pPBA-mannan immunogel exhibited a significant anticancer effect in the 4 T1 cell-inoculated mouse model, implying the potential of a codelivery system of antigens and adjuvants for effective cancer immunotherapy.
    Keywords:  Cancer immunotherapy; In situ injectable hydrogel; Mannan; Phenylboronic ester; Tumor antigen delivery
  15. Nat Commun. 2022 Mar 10. 13(1): 1255
      Currently optical-based techniques for in vivo microbial population imaging are limited by low imaging depth and highly light-scattering tissue; and moreover, are generally effective against only one specific group of bacteria. Here, we introduce an imaging and therapy strategy, in which different bacteria actively eat the glucose polymer (GP)-modified gold nanoparticles through ATP-binding cassette (ABC) transporter pathway, followed by laser irradiation-mediated aggregation in the bacterial cells. As a result, the aggregates display ~15.2-fold enhancement in photoacoustic signals and ~3.0-fold enhancement in antibacterial rate compared with non-aggregated counterparts. Significantly, the developed strategy allows ultrasensitive imaging of bacteria in vivo as low ~105 colony-forming unit (CFU), which is around two orders of magnitude lower than most optical contrast agents. We further demonstrate the developed strategy enables the detection of ~107 CFU bacteria residing within tumour or gut. This technique enables visualization and treatment of diverse bacteria, setting the crucial step forward the study of microbial ecosystem.
  16. JACS Au. 2022 Feb 28. 2(2): 357-366
      DNA nanotechnology has increasingly been used as a platform to scaffold enzymes based on its unmatched ability to structure enzymes in a desired format. The capability to organize enzymes has taken many forms from more traditional 2D pairings on individual scaffolds to recent works introducing enzyme organizations in 3D lattices. As the ability to define nanoscale structure has grown, it is critical to fully deconstruct the impact of enzyme organization at the single-scaffold level. Here, we present an open, three-dimensional (3D) DNA wireframe octahedron which is used to create a library of spatially arranged organizations of glucose oxidase and horseradish peroxidase. We explore the contribution of enzyme spacing, arrangement, and location on the 3D scaffold to cascade activity. The experiments provide insight into enzyme scaffold design, including the insignificance of scaffold sequence makeup on activity, an increase in activity at small enzyme spacings of <10 nm, and activity changes that arise from discontinuities in scaffold architecture. Most notably, the experiments allow us to determine that enzyme colocalization itself on the DNA scaffold dominates over any specific enzyme arrangement.