Articles in press have been peer-reviewed and accepted, which are not yet assigned to volumes /issues, but are citable by Digital Object Identifier (DOI).
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2020, 6(6): 223-244.
doi: 10.1007/s41048-020-00125-8
Abstract:
Artificial nanorobot is a type of robots designed for executing complex tasks at nanoscale. The nanorobot system is typically consisted of four systems, including logic control, driving, sensing and functioning. Considering the subtle structure and complex functionality of nanorobot, the manufacture of nanorobots requires designable, controllable and multi-functional nanomaterials. Here, we propose that nanozyme is a promising candidate for fabricating nanorobots due to its unique properties, including flexible designs, controllable enzyme-like activities, and nano-sized physicochemical characters. Nanozymes may participate in one system or even combine several systems of nanorobots. In this review, we summarize the advances on nanozyme-based systems for fabricating nanorobots, and prospect the future directions of nanozyme for constructing nanorobots. We hope that the unique properties of nanozymes will provide novel ideas for designing and fabricating nanorobotics.
Artificial nanorobot is a type of robots designed for executing complex tasks at nanoscale. The nanorobot system is typically consisted of four systems, including logic control, driving, sensing and functioning. Considering the subtle structure and complex functionality of nanorobot, the manufacture of nanorobots requires designable, controllable and multi-functional nanomaterials. Here, we propose that nanozyme is a promising candidate for fabricating nanorobots due to its unique properties, including flexible designs, controllable enzyme-like activities, and nano-sized physicochemical characters. Nanozymes may participate in one system or even combine several systems of nanorobots. In this review, we summarize the advances on nanozyme-based systems for fabricating nanorobots, and prospect the future directions of nanozyme for constructing nanorobots. We hope that the unique properties of nanozymes will provide novel ideas for designing and fabricating nanorobotics.
2020, 6(6): 245-255.
doi: 10.1007/s41048-020-00124-9
Abstract:
Nanozymes, nanomaterials with enzyme-like activity, have been considered as promising alternatives of natural enzymes. Molecular logic gates, which can simulate the function of the basic unit of an electronic computer, perform Boolean logic operation in response to chemical, biological, or optical signals. Recently, the combination of nanozymes and logic gates enabled bioinformation processing in a logically controllable way. In the review, recent progress in the construction of nanozyme-based logic gates integrated with their utility in sensing is introduced. Furthermore, the issues and challenges in the construction processes are discussed. It is expected the review will facilitate a comprehensive understanding of nanozyme-based logic systems.
Nanozymes, nanomaterials with enzyme-like activity, have been considered as promising alternatives of natural enzymes. Molecular logic gates, which can simulate the function of the basic unit of an electronic computer, perform Boolean logic operation in response to chemical, biological, or optical signals. Recently, the combination of nanozymes and logic gates enabled bioinformation processing in a logically controllable way. In the review, recent progress in the construction of nanozyme-based logic gates integrated with their utility in sensing is introduced. Furthermore, the issues and challenges in the construction processes are discussed. It is expected the review will facilitate a comprehensive understanding of nanozyme-based logic systems.
2020, 6(6): 256-265.
doi: 10.1007/s41048-020-00123-w
Abstract:
Deoxyribozyme (or denoted as DNAzyme), which is produced by in vitro screening technology, has gained extensive research interest in the field of biomedicine due to its high catalytic activity and structure identification. This review introduces the structural characteristics of RNA-cleaving DNAzyme and its application potential in cancer gene therapy, which plays a significant role in cancer-related gene inactivation by specifically cleaving target mRNA and inhibiting the expression of the corresponding protein. However, the low delivery efficiency and cellular uptake hindered the widespread usage of DNAzyme in gene therapy of cancers. Emerging nanotechnology holds great promise for DNAzyme to overcome these obstacles. This review mainly focuses on DNAzyme-based nanotherapeutic platforms in gene therapy of cancers, including oncogene antagonism therapy, treatment resistance gene therapy, immunogene therapy, and antiangiogenesis gene therapy. We also revealed the potential of DNAzymebased nanotherapeutic platforms as emerging cancer therapy approaches and their security issues.
Deoxyribozyme (or denoted as DNAzyme), which is produced by in vitro screening technology, has gained extensive research interest in the field of biomedicine due to its high catalytic activity and structure identification. This review introduces the structural characteristics of RNA-cleaving DNAzyme and its application potential in cancer gene therapy, which plays a significant role in cancer-related gene inactivation by specifically cleaving target mRNA and inhibiting the expression of the corresponding protein. However, the low delivery efficiency and cellular uptake hindered the widespread usage of DNAzyme in gene therapy of cancers. Emerging nanotechnology holds great promise for DNAzyme to overcome these obstacles. This review mainly focuses on DNAzyme-based nanotherapeutic platforms in gene therapy of cancers, including oncogene antagonism therapy, treatment resistance gene therapy, immunogene therapy, and antiangiogenesis gene therapy. We also revealed the potential of DNAzymebased nanotherapeutic platforms as emerging cancer therapy approaches and their security issues.
2020, 6(6): 266-277.
doi: 10.1007/s41048-020-00121-y
Abstract:
Microgravity (MG) effect is a weightlessness phenomenon caused by the distance from the ground or low gravity of other planets outside the earth's atmosphere. The various effects of MG have been corroborated in human and animal studies and modeled in cell-based analogs. However, the impact of MG on siRNA performance remains to be elucidated, which is crucial for aerospace medicine. In this study, we prepared nucleic acid nanomicelles (EAASc/siRNA) by using tri-block copolymer of PEG45- PAMA40-P(C7A36-DBA37) (EAASc) and siRNA and explored its working mechanism under simulated microgravity (SMG) condition generated by a random positioning machine (RPM). The binding ability of EAASc to siRNA and silence activity were firstly confirmed in normal gravity (NG) environment. Evaluation of PLK1 mRNA expression revealed that gene inhibition efficiencies were increased by 28.7% (HepG2) and 28.9% (A549) under SMG condition, compared with those under NG condition. In addition, mechanism exploration indicated that morphology and migration capability of cancer cells were significantly changed, the internalization of EAASc/siRNA by cells was magnified when the cells were incubated with RPM. No significant difference was observed regarding the expression profiles of genes involved in RNA interference (RNAi) pathway, including Ago2, Dicer, TRBP, and so on. Taken together, siRNA activity was elevated under SMG condition owning to increased cellular internalization. This study, for the first time to our knowledge, provides valuable theory for development and application of siRNA therapeutic in space in the future.
Microgravity (MG) effect is a weightlessness phenomenon caused by the distance from the ground or low gravity of other planets outside the earth's atmosphere. The various effects of MG have been corroborated in human and animal studies and modeled in cell-based analogs. However, the impact of MG on siRNA performance remains to be elucidated, which is crucial for aerospace medicine. In this study, we prepared nucleic acid nanomicelles (EAASc/siRNA) by using tri-block copolymer of PEG45- PAMA40-P(C7A36-DBA37) (EAASc) and siRNA and explored its working mechanism under simulated microgravity (SMG) condition generated by a random positioning machine (RPM). The binding ability of EAASc to siRNA and silence activity were firstly confirmed in normal gravity (NG) environment. Evaluation of PLK1 mRNA expression revealed that gene inhibition efficiencies were increased by 28.7% (HepG2) and 28.9% (A549) under SMG condition, compared with those under NG condition. In addition, mechanism exploration indicated that morphology and migration capability of cancer cells were significantly changed, the internalization of EAASc/siRNA by cells was magnified when the cells were incubated with RPM. No significant difference was observed regarding the expression profiles of genes involved in RNA interference (RNAi) pathway, including Ago2, Dicer, TRBP, and so on. Taken together, siRNA activity was elevated under SMG condition owning to increased cellular internalization. This study, for the first time to our knowledge, provides valuable theory for development and application of siRNA therapeutic in space in the future.
2020, 6(6): 278-289.
doi: 10.1007/s41048-020-00120-z
Abstract:
Small interfering RNA (siRNA)-based RNA interference has emerged as a promising therapeutic strategy for the treatment of a wide range of incurable diseases. However, the safe and effective delivery of siRNA therapeutics into the interior of target cells remains challenging. Here, we disclosed novel amphiphilic peptide dendrimers (AmPDs) that composed of hydrophobic two lipid-like alkyl chains and hydrophilic poly(lysine) dendrons with different generations (2C18-KK2 and 2C18-KK2K4) as nanovehicles for siRNA delivery. These AmPDs are able to self-assemble into supramolecular nanoassemblies that are capable of entrapping siRNA molecules into nanoparticles to protect siRNA from enzymatic degradation and promote efficient intracellular uptake without evident toxicity. Interestingly, by virtue of the optimal balance of hydrophobic lipid-like entity and hydrophilic poly(lysine) dendron generations, AmPD 2C18-KK2K4 bearing bigger hydrophilic dendron can package siRNA to form stable, but more ready to disassemble complexes, thereby resulting in more efficient siRNA releasing and better gene silencing effect in comparison with AmPD 2C18-KK2 bearing smaller dendron. Additional studies confirmed that 2C18-KK2K4 can capitalize on the advantages of lipid and peptide dendrimer vectors for effective siRNA delivery. Collectively, our AmPD-based nanocarriers indeed represent a safe and effective siRNA delivery system. Our findings also provide a new perspective on the modulation of selfassembly amphiphilic peptide dendrimers for the functional and adaptive delivery of siRNA therapeutics.
Small interfering RNA (siRNA)-based RNA interference has emerged as a promising therapeutic strategy for the treatment of a wide range of incurable diseases. However, the safe and effective delivery of siRNA therapeutics into the interior of target cells remains challenging. Here, we disclosed novel amphiphilic peptide dendrimers (AmPDs) that composed of hydrophobic two lipid-like alkyl chains and hydrophilic poly(lysine) dendrons with different generations (2C18-KK2 and 2C18-KK2K4) as nanovehicles for siRNA delivery. These AmPDs are able to self-assemble into supramolecular nanoassemblies that are capable of entrapping siRNA molecules into nanoparticles to protect siRNA from enzymatic degradation and promote efficient intracellular uptake without evident toxicity. Interestingly, by virtue of the optimal balance of hydrophobic lipid-like entity and hydrophilic poly(lysine) dendron generations, AmPD 2C18-KK2K4 bearing bigger hydrophilic dendron can package siRNA to form stable, but more ready to disassemble complexes, thereby resulting in more efficient siRNA releasing and better gene silencing effect in comparison with AmPD 2C18-KK2 bearing smaller dendron. Additional studies confirmed that 2C18-KK2K4 can capitalize on the advantages of lipid and peptide dendrimer vectors for effective siRNA delivery. Collectively, our AmPD-based nanocarriers indeed represent a safe and effective siRNA delivery system. Our findings also provide a new perspective on the modulation of selfassembly amphiphilic peptide dendrimers for the functional and adaptive delivery of siRNA therapeutics.
2020, 6(6): 290-298.
doi: 10.1007/s41048-020-00122-x
Abstract:
Cancer immunotherapy has made recent breakthrough, including immune checkpoint blockade (ICB) that inhibits immunosuppressive checkpoints such as programmed cell death protein 1 (PD-1) and programmed death-ligand 1 (PD-L1). However, most cancer patients do not durably respond to ICB. To predict ICB responses for patient stratification, conventional immunostaining has been used to analyze the PD-L1 expression level on biopsied tumor tissues but has limitations of invasiveness and tumor heterogeneity. Recently, PD-L1 levels on tumor cell exosomes showed the potential to predict ICB response. Here, we developed a non-invasive, sensitive, and fast assay, termed as exosome-hybridization chain reaction (ExoHCR), to analyze tumor cell exosomal PD-L1 levels. First, using aCD63-conjugated magnetic beads, we isolated exosomes from B16F10 melanoma and CT26 colorectal cancer cells that were immunostimulated to generate PD-L1-positive exosomes. Exosomes were then incubated with a conjugate of PD-L1 antibody with an HCR trigger DNA (T), in which one aPD-L1-T conjugate carried multiple copies of T. Next, a pair of metastable fluorophore-labeled hairpin DNA (H1 and H2) were added, allowing T on aPD-L1-T to initiate HCR in situ on bead-conjugated exosome surfaces. By flow cytometric analysis of the resulting beads, relative to aPD-L1-fluorophore conjugates, ExoHCR amplified the fluorescence signal intensities for exosome detection by 3-7 times in B16F10 cells and CT26 cells. Moreover, we validated the biostability of ExoHCR in culture medium supplemented with 50% FBS. These results suggest the potential of ExoHCR for non-invasive, sensitive, and fast PD-L1 exosomal profiling in patient stratification of cancer immunotherapy.
Cancer immunotherapy has made recent breakthrough, including immune checkpoint blockade (ICB) that inhibits immunosuppressive checkpoints such as programmed cell death protein 1 (PD-1) and programmed death-ligand 1 (PD-L1). However, most cancer patients do not durably respond to ICB. To predict ICB responses for patient stratification, conventional immunostaining has been used to analyze the PD-L1 expression level on biopsied tumor tissues but has limitations of invasiveness and tumor heterogeneity. Recently, PD-L1 levels on tumor cell exosomes showed the potential to predict ICB response. Here, we developed a non-invasive, sensitive, and fast assay, termed as exosome-hybridization chain reaction (ExoHCR), to analyze tumor cell exosomal PD-L1 levels. First, using aCD63-conjugated magnetic beads, we isolated exosomes from B16F10 melanoma and CT26 colorectal cancer cells that were immunostimulated to generate PD-L1-positive exosomes. Exosomes were then incubated with a conjugate of PD-L1 antibody with an HCR trigger DNA (T), in which one aPD-L1-T conjugate carried multiple copies of T. Next, a pair of metastable fluorophore-labeled hairpin DNA (H1 and H2) were added, allowing T on aPD-L1-T to initiate HCR in situ on bead-conjugated exosome surfaces. By flow cytometric analysis of the resulting beads, relative to aPD-L1-fluorophore conjugates, ExoHCR amplified the fluorescence signal intensities for exosome detection by 3-7 times in B16F10 cells and CT26 cells. Moreover, we validated the biostability of ExoHCR in culture medium supplemented with 50% FBS. These results suggest the potential of ExoHCR for non-invasive, sensitive, and fast PD-L1 exosomal profiling in patient stratification of cancer immunotherapy.
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