bims-drudre Biomed News
on Targeted drug delivery and programmed release mechanisms
Issue of 2021‒01‒31
seventeen papers selected by
Ceren Kimna
Technical University of Munich


  1. ACS Nano. 2021 Jan 25.
    Kim T, Nam K, Kim YM, Yang K, Roh YH.
      Due to powerful breakthroughs in nanotechnology, smart delivery mechanisms have rapidly emerged for use in diverse applications across biomedical research and therapeutic development. Recent efforts toward understanding stimuli-responsive strategies have led to substantial improvements in their conceptual application and in vitro efficiency. Because disease targets for therapy are often localized in specific cells, organs, or tissues, an enhanced permeability and retention (EPR)-based strategy remains inadequate for accurate drug delivery and release to target regions, resulting in an insufficient drug concentration reaching the target region and undesired side effects. To address these issues, more precise and remote-controlled stimuli-responsive systems, which recognize and react to changes in the pathophysiological microenvironment, were recently elucidated as feasible on-demand drug-delivery systems. In this Perspective, we focus on progress toward stimuli-responsive drug-delivery systems that utilize dynamic DNA molecules by exploiting DNA nanotechnology. DNA structures can be precisely reconfigured by external and internal stimuli to drive the release of a loaded drug in a target region with appropriate microenvironments. We describe the chemical, physical, and biological engineering principles and strategies for constructing DNA-assisted nanocarriers. We also provide a summary of smart nanocarrier systems, organized with respect to the structural changes in the DNA strand in the microenvironment, resulting from changes in pH and temperature and the presence of intracellular oligonucleotides. To do so, we highlight recent advances in related biomedical research and applications as well as discuss major challenges and opportunities for DNA-assisted nanocarriers to guide the development of future in vivo therapies and clinical translation strategies.
    DOI:  https://doi.org/10.1021/acsnano.0c08905
  2. Adv Mater. 2021 Jan 27. e2006116
    Gao X, Li S, Ding F, Liu X, Wu Y, Li J, Feng J, Zhu X, Zhang C.
      Immunotherapy is recognized as one of the most promising approaches to treat cancers. However, its effect in glioblastoma (GBM) treatment is insufficient, which can in part be attributed to the immunosuppressive tumor microenvironment (TME). Microglia and macrophages are the main immune infiltrating cells in the TME of GBM. Unfortunately, instead of initiating the anti-tumor response, GBM-infiltrating microglia and macrophages switch to a tumor-promoting phenotype (M2), and support tumor growth, angiogenesis, and immunosuppression by the release of cytokines. In this work, a virus-mimicking membrane-coated nucleic acid nanogel Vir-Gel embedded with therapeutic miRNA is developed, which can reprogram microglia and macrophages from a pro-invasive M2 phenotype to an anti-tumor M1 phenotype. By mimicking the virus infection process, Vir-Gel significantly enhances the targetability and cell uptake efficiency of the miR155-bearing nucleic acid nanogel. In vivo evaluations demonstrate that Vir-Gel apparently prolongs the circulation lifetime of miR155 and endows it with an active tumor-targeting capability and excellent tumor inhibition efficacy. Owing to its noninvasive feature and effective delivery capability, the virus-mimicking nucleic acid nanogel provides a general and convenient platform that can successfully treat a wide range of diseases.
    Keywords:  glioblastoma; miRNA; nucleic acid nanogels; phenotype reprogramming; tumor microenvironment
    DOI:  https://doi.org/10.1002/adma.202006116
  3. Nanomaterials (Basel). 2021 Jan 22. pii: 289. [Epub ahead of print]11(2):
    Bloise N, Okkeh M, Restivo E, Della Pina C, Visai L.
      Nanotechnology is in the spotlight of therapeutic innovation, with numerous advantages for tumor visualization and eradication. The end goal of the therapeutic use of nanoparticles, however, remains distant due to the limitations of nanoparticles to target cancer tissue. The functionalization of nanosystem surfaces with biological ligands is a major strategy for directing the actions of nanomaterials specifically to tumor cells. Cancer formation and metastasis are accompanied by profound alterations in protein glycosylation. Hence, the detection and targeting of aberrant glycans are of great value in cancer diagnosis and therapy. In this review, we provide a brief update on recent progress targeting aberrant glycosylation by functionalizing nanoparticles with glycan-binding molecules (with a special focus on lectins and anti-glycan antibodies) to improve the efficacy of nanoparticles in cancer targeting, diagnosis, and therapy and outline the challenges and limitations in implementing this approach. We envision that the combination of nanotechnological strategies and cancer-associated glycan targeting could remodel the field of cancer diagnosis and therapy, including immunotherapy.
    Keywords:  aberrant glycosylation; antibody; glycan-binding molecules; lectin; nanomedicine; tumor targeting and therapy
    DOI:  https://doi.org/10.3390/nano11020289
  4. Science. 2021 Jan 25. pii: eabf4830. [Epub ahead of print]
    Rappazzo CG, Tse LV, Kaku CI, Wrapp D, Sakharkar M, Huang D, Deveau LM, Yockachonis TJ, Herbert AS, Battles MB, O'Brien CM, Brown ME, Geoghegan JC, Belk J, Peng L, Yang L, Hou Y, Scobey TD, Burton DR, Nemazee D, Dye JM, Voss JE, Gunn BM, McLellan JS, Baric RS, Gralinski LE, Walker LM.
      The recurrent zoonotic spillover of coronaviruses (CoVs) into the human population underscores the need for broadly active countermeasures. We employed a directed evolution approach to engineer three SARS-CoV-2 antibodies for enhanced neutralization breadth and potency. One of the affinity-matured variants, ADG-2, displays strong binding activity to a large panel of sarbecovirus receptor binding domains (RBDs) and neutralizes representative epidemic sarbecoviruses with high potency. Structural and biochemical studies demonstrate that ADG-2 employs a distinct angle of approach to recognize a highly conserved epitope overlapping the receptor binding site. In immunocompetent mouse models of SARS and COVID-19, prophylactic administration of ADG-2 provided complete protection against respiratory burden, viral replication in the lungs, and lung pathology. Altogether, ADG-2 represents a promising broad-spectrum therapeutic candidate against clade 1 sarbecoviruses.
    DOI:  https://doi.org/10.1126/science.abf4830
  5. Nat Commun. 2021 Jan 29. 12(1): 678
    Wang Y, Cheng H, Liu Y, Liu Y, Wen X, Zhang K, Ni X, Gao N, Fan L, Zhang Z, Liu J, Chen J, Wang L, Guo Y, Zheng P, Wang M, Sun J, Ma Y.
      Reprogramming complex cellular metabolism requires simultaneous regulation of multigene expression. Ex-situ cloning-based methods are commonly used, but the target gene number and combinatorial library size are severely limited by cloning and transformation efficiencies. In-situ methods such as multiplex automated genome engineering (MAGE) depends on high-efficiency transformation and incorporation of heterologous DNA donors, which are limited to few microorganisms. Here, we describe a Base Editor-Targeted and Template-free Expression Regulation (BETTER) method for simultaneously diversifying multigene expression. BETTER repurposes CRISPR-guided base editors and in-situ generates large numbers of genetic combinations of diverse ribosome binding sites, 5' untranslated regions, or promoters, without library construction, transformation, and incorporation of DNA donors. We apply BETTER to simultaneously regulate expression of up to ten genes in industrial and model microorganisms Corynebacterium glutamicum and Bacillus subtilis. Variants with improved xylose catabolism, glycerol catabolism, or lycopene biosynthesis are respectively obtained. This technology will be useful for large-scale fine-tuning of multigene expression in both genetically tractable and intractable microorganisms.
    DOI:  https://doi.org/10.1038/s41467-021-21003-y
  6. Adv Mater. 2021 Jan 25. e2007888
    Liu J, Hu F, Wu M, Tian L, Gong F, Zhong X, Chen M, Liu Z, Liu B.
      Radiodynamic therapy (RDT), an emerging therapeutic approach for cancer treatment by employing ionizing irradiation to induce localized photodynamic therapy (PDT) can overcome the drawbacks of the limited penetration depth for traditional PDT and the unconcentrated energy in the tumor for traditional radiotherapy (RT). Taking advantage of aggregation-induced emission (AIE) photosensitizers with bright fluorescence and efficient singlet oxygen production in the aggregate state, Hf-AIE coordination polymer nanoparticles (CPNs), which show both strong RT and RDT effect under X-ray irradiation, are developed. Furthermore, to enhance the tumor accumulation and prolong the tumor retention of the CPNs, bioorthogonal click chemistry is applied in the system through coupling between dibenzocyclooctyne (DBCO)-modified CPNs (Hf-AIE-PEG-DBCO) (PEG: poly(ethylene glycol)) and azide groups on the cell membrane formed by metabolic glycoengineering. Thanks to the high penetration of X-ray irradiation, the bioorthogonal-assisted RT and RDT combination therapy realizes significant killing of cancer cells without showing noticeable biotoxicity after intravenous administration of CPNs.
    Keywords:  aggregation-induced emission; biorthogonal reaction; coordination polymer nanoparticles; radiodynamic therapy; radiotherapy
    DOI:  https://doi.org/10.1002/adma.202007888
  7. ACS Nano. 2021 Jan 25.
    Arulkumaran N, Lanphere C, Gaupp C, Burns JR, Singer M, Howorka S.
      DNA nanotechnology produces precision nanostructures of defined chemistry. Expanding their use in biomedicine requires designed biomolecular interaction and function. Of topical interest are DNA nanostructures that function as vaccines with potential advantages over nonstructured nucleic acids in terms of serum stability and selective interaction with human immune cells. Here, we describe how compact DNA nanobarrels bind with a 400-fold selectivity via membrane anchors to white blood immune cells over erythrocytes, without affecting cell viability. The selectivity is based on the preference of the cholesterol lipid anchor for the more fluid immune cell membranes compared to the lower membrane fluidity of erythrocytes. Compacting DNA into the nanostructures gives rise to increased serum stability. The DNA barrels furthermore functionally modulate white blood cells by suppressing the immune response to pro-inflammatory endotoxin lipopolysaccharide. This is likely due to electrostatic or steric blocking of toll-like receptors on white blood cells. Our findings on immune cell-specific DNA nanostructures may be applied for vaccine development, immunomodulatory therapy to suppress septic shock, or the targeting of bioactive substances to immune cells.
    Keywords:  DNA; DNA nanotechnology; bilayer membrane; immunomodulation; lipids; nanostructures; white blood cells
    DOI:  https://doi.org/10.1021/acsnano.0c07915
  8. Sci Adv. 2021 Jan;pii: eabe0337. [Epub ahead of print]7(5):
    Phan TS, Schink L, Mann J, Merk VM, Zwicky P, Mundt S, Simon D, Kulms D, Abraham S, Legler DF, Noti M, Brunner T.
      Glucocorticoids (GC), synthesized by the 11β-hydroxylase (Cyp11b1), control excessive inflammation through immunosuppressive actions. The skin was proposed to regulate homeostasis by autonomous GC production in keratinocytes. However, their immunosuppressive capacity and clinical relevance remain unexplored. Here, we demonstrate the potential of skin-derived GC and their role in the regulation of physiological and prevalent inflammatory skin conditions. In line with 11β-hydroxylase deficiency in human inflammatory skin disorders, genetic in vivo Cyp11b1 ablation and long-term GC deficiency in keratinocytes primed the murine skin immune system resulting in spontaneous skin inflammation. Deficient skin GC in experimental models for inflammatory skin disorders led to exacerbated contact hypersensitivity and psoriasiform skin inflammation accompanied by decreased regulatory T cells and the involvement of unconventional T cells. Our findings provide insights on how skin homeostasis and pathology are critically regulated by keratinocyte-derived GC, emphasizing the immunoregulatory potential of endogenous GC in the regulation of epithelial immune microenvironment.
    DOI:  https://doi.org/10.1126/sciadv.abe0337
  9. Onco Targets Ther. 2021 ;14 455-467
    Rodrigues-Junior DM, Pelarin MFA, Nader HB, Vettore AL, Pinhal MAS.
      Introduction: Multiple myeloma (MM) remains an incurable disease, and patient survival requires a better understanding of this malignancy's molecular aspects. Heparanase (HPSE) is highly expressed in aggressive MM cells and related to tumor growth, metastasis, and bortezomib (BTZ) resistance. Thus, targeting HPSE seems to be a promising approach for MM treatment, and because microRNAs (miRNAs) have emerged as potential regulators of HPSE expression, the use of extracellular vesicles (EVs) can allow the efficient delivery of therapeutic miRNAs.Methods: We used prediction algorithms to identify potential miRNAs that regulate negatively HPSE expression. RT-qPCR was performed to assess miRNAs and HPSE expression in MM lines (U266 and RPMI-8226). Synthetic miRNA mimics were electroporated in MM cells to understand the miRNA contribution in HPSE expression, glycosaminoglycans (GAGs) profile, cell proliferation, and cell death induced by BTZ. EVs derived from HEK293T cells were engineered with miRNAs to evaluate their therapeutic potential combined with BTZ.
    Results: It revealed a direct association between BTZ sensitivity, HPSE, and miR-1252-5p expressions. Moreover, overexpression of miR-1252-5p significantly reduced HPSE expression and HPSE enzymatic activity in MM cells. The higher level of miR-1252-5p was correlated with a reduction of cell viability and higher sensitivity to BTZ. Further, EVs carrying miR-1252-5p increased MM cells' sensitivity to BTZ treatment.
    Conclusion: These results showed that miR-1252-5p could negatively regulate HPSE in MM, indicating the use of EVs carrying miR-1252-5p as a potential novel BTZ sensitization approach in MM cells.
    Keywords:  bortezomib; cancer; exosomes; extracellular vesicles; heparanase; microRNA; multiple myeloma
    DOI:  https://doi.org/10.2147/OTT.S286751
  10. Trends Mol Med. 2021 Jan 21. pii: S1471-4914(20)30329-4. [Epub ahead of print]
    Dan J, Memczak S, Izpisua Belmonte JC.
      Genome editing holds great promise for treating a range of human genetic diseases. While emerging clustered regularly interspaced short-palindromic repeats (CRISPR) technologies allow editing of the nuclear genome, it is still not possible to precisely manipulate mitochondrial DNA (mtDNA). Here, we summarize past developments and recent advances in nuclear and mitochondrial genome editing.
    Keywords:  gene therapy; genome editing; mitochondria; translational medicine
    DOI:  https://doi.org/10.1016/j.molmed.2020.12.005
  11. Adv Sci (Weinh). 2021 Jan;8(2): 2003041
    Fang X, Wu X, Li Z, Jiang L, Lo WS, Chen G, Gu Y, Wong WT.
      Metal phosphorous trichalcogenides (MPX3) are novel 2D nanomaterials that have recently been exploited as efficient photothermal-chemodynamic agents for cancer therapy. As a representative MPX3, FePSe3 has the potential to be developed as magnetic resonance imaging (MRI) and photoacoustic imaging (PAI) agents due to the composition of Fe and the previously revealed PA signal. Here, a FePSe3-based theranostic agent, FePSe3@APP@CCM, loaded with anti-PD-1 peptide (APP) as the inner component and CT26 cancer cell membrane (CCM) as the outer shell is reported, which acts as a multifunctional agent for MR and PA imaging and photothermal and immunotherapy against cancer. FePSe3@APP@CCM induces highly efficient tumor ablation and suppresses tumor growth by photothermal therapy under near-infrared laser excitation, which further activates immune responses. Moreover, APP blocks the PD-1/PD-L1 pathway to activate cytotoxic T cells, causing strong anticancer immunity. The combined therapy significantly prolongs the lifespan of experimental mice. The multimodal imaging and synergistic therapeutic effects of PTT and its triggered immune responses and APP-related immunotherapy are clearly demonstrated by in vitro and in vivo experiments. This work demonstrates the potential of MPX3-based biomaterials as novel theranostic agents.
    Keywords:  FePSe3 nanosheets; PD‐1 blockade; cancer photothermal–immune therapy; metal phosphorus trichalcogenides; multimodal imaging
    DOI:  https://doi.org/10.1002/advs.202003041
  12. Adv Drug Deliv Rev. 2021 Jan 20. pii: S0169-409X(21)00018-1. [Epub ahead of print]
    Liu R, Zuo R, Hudalla GA.
      A grand challenge in drug delivery is providing the right dose, at the right anatomic location, for the right duration of time to maximize therapeutic efficacy while minimizing off-target toxicity and other deleterious side-effects. Two general modalities are receiving broad attention for localized drug delivery. In the first, referred to as "targeted accumulation", drugs or drug carriers are engineered to have targeting moieties that promote their accumulation at a specific tissue site from circulation. In the second, referred to as "local anchoring", drugs or drug carriers are inserted directly into the tissue site of interest where they persist for a specified duration of time. This review surveys recent advances in harnessing molecular recognition between proteins, peptides, nucleic acids, lipids, and carbohydrates to mediate targeted accumulation and local anchoring of drugs and drug carriers.
    Keywords:  Carbohydrates; Injectable materials; Localized drug delivery; Peptides; Proteins; Targeted drug delivery
    DOI:  https://doi.org/10.1016/j.addr.2021.01.008
  13. Nat Biomed Eng. 2021 Jan 25.
    Song X, Ji H, Li Y, Xiong Y, Qiu L, Zhong R, Tian M, Kizhakkedathu JN, Su B, Wei Q, Zhao W, Zhao C.
      During extracorporeal blood purification, anticoagulants are administered to prevent thrombogenesis. However, haemorrhagic complications owing to near-complete inactivation of blood coagulation and delayed recovery of haemostasis pose serious risks to patients. Here, we show in vitro and in beagle dogs that hydrogel microspheres that adsorb the coagulation factors VIII, IX and XI provide transient blood thinning when placed in the extracorporeal circuit before blood purification. The microspheres inhibited the activities of the coagulation factors by levels (~8-30%) similar to those occurring in mild haemophilia. On its reintroduction into the animal, the purified pseudo-haemophilic blood favoured faster recovery of haemostasis. The transient blood-thinning strategy may increase the safety of clinical blood-purification procedures.
    DOI:  https://doi.org/10.1038/s41551-020-00673-x
  14. Small. 2021 Jan 27. e2004573
    Stamatopoulos K, Kafourou V, Batchelor HK, Konteles SJ.
      Despite several decades of research into encapsulation of bacteria, most of the proposed technologies are in the form of immobilized cultures. In this work, sporopollenin exine capsules (SECs) opened, using silica particles which act as pressing micro-probes, and loaded with Lactobacillus casei (L. casei) cells, are described for the first time. The proposed encapsulation provided ≈30× higher encapsulation yield (30.87%), compared to direct compression of SECs (0.99%). Encapsulated L. casei cells show 1.21- and 2.25-folds higher viability compared to free cells, in in vitro simulated fasted and fed media representing the human gastrointestinal (GI) tract, respectively. Encapsulated L. casei can proliferate inside the SECs, generating enough pressure to cause the SECs to burst and release the viable and metabolically active cells. The noticeable difference with the application of the SECs as a means of encapsulation is that the SECs may act as a bioreactor and provide time for the encapsulated cells to multiply thousands of times before being released, following the SEC's burst. The unique advantages of SECs alongside the proposed encapsulation method, demonstrates the potential application of SECs as delivery system of probiotics to the distal part of the human GI tract.
    Keywords:  flow cytometry; lactobacillus casei; microencapsulation; mrs plate count; probiotics; scanning electron microscope; sporopollenin
    DOI:  https://doi.org/10.1002/smll.202004573
  15. Acta Biomater. 2021 Jan 21. pii: S1742-7061(21)00054-4. [Epub ahead of print]
    Hoang P, Ma Z.
      Organoids are miniature models of organs to recapitulate spatiotemporal cellular organization and tissue functionality. The production of organoids has revolutionized the field of developmental biology, providing the possibility to study and guide human development and diseases in a dish. More recently, novel biomaterial-based culture systems demonstrated the feasibility and versatility to engineer and produce the organoids in a consistent and reproducible manner. By engineering proper tissue microenvironment, functional organoids have been able to exhibit spatial-distinct tissue patterning and morphogenesis. This review will focus on enabling technologies in the field of organoid engineering, including the control of biochemical and biophysical cues via hydrogels, as well as size and geometry control via microwell and microfabrication techniques. In addition, this review discusses the enhancement of organoid systems for therapeutic applications using biofabrication and organoid-on-chip platforms, which facilitate the assembly of complex organoid systems for in vitro modeling of development and diseases.
    Keywords:  Biomaterials; Organoids; Self-Organization; Spatial Patterning; Stem cell engineering
    DOI:  https://doi.org/10.1016/j.actbio.2021.01.026
  16. Front Robot AI. 2019 ;6 126
    Christianson C, Bayag C, Li G, Jadhav S, Giri A, Agba C, Li T, Tolley MT.
      Robots for underwater exploration are typically comprised of rigid materials and driven by propellers or jet thrusters, which consume a significant amount of power. Large power consumption necessitates a sizeable battery, which limits the ability to design a small robot. Propellers and jet thrusters generate considerable noise and vibration, which is counterproductive when studying acoustic signals or studying timid species. Bioinspired soft robots provide an approach for underwater exploration in which the robots are comprised of compliant materials that can better adapt to uncertain environments and take advantage of design elements that have been optimized in nature. In previous work, we demonstrated that frameless DEAs could use fluid electrodes to apply a voltage to the film and that effective locomotion in an eel-inspired robot could be achieved without the need for a rigid frame. However, the robot required an off-board power supply and a non-trivial control signal to achieve propulsion. To develop an untethered soft swimming robot powered by DEAs, we drew inspiration from the jellyfish and attached a ring of frameless DEAs to an inextensible layer to generate a unimorph structure that curves toward the passive side to generate power stroke, and efficiently recovers the original configuration as the robot coasts. This swimming strategy simplified the control system and allowed us to develop a soft robot capable of untethered swimming at an average speed of 3.2 mm/s and a cost of transport of 35. This work demonstrates the feasibility of using DEAs with fluid electrodes for low power, silent operation in underwater environments.
    Keywords:  artificial muscles; bioinspired robotics; dielectric elastomer actuators; jellyfish swimming; soft robotics
    DOI:  https://doi.org/10.3389/frobt.2019.00126
  17. ACS Appl Mater Interfaces. 2021 Jan 26.
    Zhao H, Li T, Yao C, Gu Z, Liu C, Li J, Yang D.
      MicroRNA (miRNA) represents a promising class of therapeutic nucleic acid drugs, while delivery challenges remain that impede the advancement of miRNA therapy, largely because of in vivo instability and low delivery efficiency. Herein, we discover the dual roles of metal-organic framework (MOF) nanoparticles (ZIF-8) as nanocarriers for miRNA delivery and adjuvants for chemodynamic therapy. The miR-34a-m@ZIF-8 complex demonstrated efficient cellular uptake and lysosomal stimuli-responsive miRNA release. Zn2+ triggered the generation of reactive oxygen species, which consequently induced apoptosis of tumor cells. Released miR-34a-m led to a remarkable decrease in expression of Bcl-2 at both mRNA and protein levels and enhanced cancer cell apoptosis. In vivo experiments showed high efficacy of using miR-34a-m@ZIF-8 to suppress tumor growth via synergistic gene/chemodynamic therapy in a mouse model of triple-negative breast cancer. Our work demonstrates MOFs as a promising nanoplatform for efficient synergetic gene/chemodynamic therapy.
    Keywords:  chemodynamic therapy; gene therapy; metal−organic framework; microRNA delivery; triple-negative breast cancer
    DOI:  https://doi.org/10.1021/acsami.0c21006