Systematic Study in Mammalian Cells Showing No Adverse Response to Tetrahedral DNA Nanostructure

The advent of DNA technology has demonstrated great potential in a wide range of applications, especially in the field of biology and biomedicine. However, current understanding of the toxicological effects and cellular responses of DNA nanostructures remains to be improved. Here, we chose tetrahedral DNA nanostructures (TDNs), a type of nanocarriers for delivering molecular drugs, as a model for systematic live-cell analysis of the biocompatibility of TDNs to normal bronchial epithelial cells, carcinoma cells, and macrophage. We found that the interaction behaviors of TDNs in different cell lines were very different, whereas after internalization, most of the TDNs in diverse cell lines were positioned to lysosomes. By a systematic assessment of cell responses after TDN exposure to various cells, we demonstrate that internalized TDNs have good innate biocompatibility. Interestingly, we found that TDN-bearing cells would not affect the cell cycle progression and accompany cell division and that TDNs were separated equally into two daughter cells. This study improves our understanding of the interaction of DNA nanostructures with living systems and their biocompatibility, which will be helpful for further designing DNA nanostructures for biomedical applications

Systematic Study in Mammalian Cells Showing No Adverse Response to Tetrahedral DNA Nanostructure

The advent of DNA technology has demonstrated great potential in a wide range of applications, especially in the field of biology and biomedicine. However, current understanding of the toxicological effects and cellular responses of DNA nanostructures remains to be improved. Here, we chose tetrahedral DNA nanostructures (TDNs), a type of nanocarriers for delivering molecular drugs, as a model for systematic live-cell analysis of the biocompatibility of TDNs to normal bronchial epithelial cells, carcinoma cells, and macrophage. We found that the interaction behaviors of TDNs in different cell lines were very different, whereas after internalization, most of the TDNs in diverse cell lines were positioned to lysosomes. By a systematic assessment of cell responses after TDN exposure to various cells, we demonstrate that internalized TDNs have good innate biocompatibility. Interestingly, we found that TDN-bearing cells would not affect the cell cycle progression and accompany cell division and that TDNs were separated equally into two daughter cells. This study improves our understanding of the interaction of DNA nanostructures with living systems and their biocompatibility, which will be helpful for further designing DNA nanostructures for biomedical applications

Systematic Study in Mammalian Cells Showing No Adverse Response to Tetrahedral DNA Nanostructure

The advent of DNA technology has demonstrated great potential in a wide range of applications, especially in the field of biology and biomedicine. However, current understanding of the toxicological effects and cellular responses of DNA nanostructures remains to be improved. Here, we chose tetrahedral DNA nanostructures (TDNs), a type of nanocarriers for delivering molecular drugs, as a model for systematic live-cell analysis of the biocompatibility of TDNs to normal bronchial epithelial cells, carcinoma cells, and macrophage. We found that the interaction behaviors of TDNs in different cell lines were very different, whereas after internalization, most of the TDNs in diverse cell lines were positioned to lysosomes. By a systematic assessment of cell responses after TDN exposure to various cells, we demonstrate that internalized TDNs have good innate biocompatibility. Interestingly, we found that TDN-bearing cells would not affect the cell cycle progression and accompany cell division and that TDNs were separated equally into two daughter cells. This study improves our understanding of the interaction of DNA nanostructures with living systems and their biocompatibility, which will be helpful for further designing DNA nanostructures for biomedical applications

Systematic Study in Mammalian Cells Showing No Adverse Response to Tetrahedral DNA Nanostructure

The advent of DNA technology has demonstrated great potential in a wide range of applications, especially in the field of biology and biomedicine. However, current understanding of the toxicological effects and cellular responses of DNA nanostructures remains to be improved. Here, we chose tetrahedral DNA nanostructures (TDNs), a type of nanocarriers for delivering molecular drugs, as a model for systematic live-cell analysis of the biocompatibility of TDNs to normal bronchial epithelial cells, carcinoma cells, and macrophage. We found that the interaction behaviors of TDNs in different cell lines were very different, whereas after internalization, most of the TDNs in diverse cell lines were positioned to lysosomes. By a systematic assessment of cell responses after TDN exposure to various cells, we demonstrate that internalized TDNs have good innate biocompatibility. Interestingly, we found that TDN-bearing cells would not affect the cell cycle progression and accompany cell division and that TDNs were separated equally into two daughter cells. This study improves our understanding of the interaction of DNA nanostructures with living systems and their biocompatibility, which will be helpful for further designing DNA nanostructures for biomedical applications

Design, Synthesis, and Biological Evaluation of Potent and Selective PROTAC Degraders of Oncogenic KRAS^G12D

KRASG12D, the most frequent KRAS oncogenic mutation, is a promising target for cancer therapy. Herein, we report the design, synthesis, and biological evaluation of a series of KRASG12D PROTACs by connecting the analogues of MRTX1133 and the VHL ligand. Structural modifications of the linker moiety and KRAS inhibitor part suggested a critical role of membrane permeability in the degradation activity of the KRASG12D PROTACs. Mechanism studies with the representative compound 8o demonstrated that the potent, rapid, and selective degradation of KRASG12D induced by 8o was via a VHL- and proteasome-dependent manner. This compound selectively and potently suppressed the growth of multiple KRASG12D mutant cancer cells, displayed favorable pharmacokinetic and pharmacodynamic properties in mice, and showed significant antitumor efficacy in the AsPC-1 xenograft mouse model. Further optimization of 8o appears to be promising for the development of a new chemotherapy for KRASG12D-driven cancers as the complementary therapeutic strategy to KRAS inhibition

Design, Synthesis, and Biological Evaluation of Potent and Selective PROTAC Degraders of Oncogenic KRAS^G12D

KRASG12D, the most frequent KRAS oncogenic mutation, is a promising target for cancer therapy. Herein, we report the design, synthesis, and biological evaluation of a series of KRASG12D PROTACs by connecting the analogues of MRTX1133 and the VHL ligand. Structural modifications of the linker moiety and KRAS inhibitor part suggested a critical role of membrane permeability in the degradation activity of the KRASG12D PROTACs. Mechanism studies with the representative compound 8o demonstrated that the potent, rapid, and selective degradation of KRASG12D induced by 8o was via a VHL- and proteasome-dependent manner. This compound selectively and potently suppressed the growth of multiple KRASG12D mutant cancer cells, displayed favorable pharmacokinetic and pharmacodynamic properties in mice, and showed significant antitumor efficacy in the AsPC-1 xenograft mouse model. Further optimization of 8o appears to be promising for the development of a new chemotherapy for KRASG12D-driven cancers as the complementary therapeutic strategy to KRAS inhibition

Design, Synthesis, and Biological Evaluation of Potent and Selective PROTAC Degraders of Oncogenic KRAS^G12D

KRASG12D, the most frequent KRAS oncogenic mutation, is a promising target for cancer therapy. Herein, we report the design, synthesis, and biological evaluation of a series of KRASG12D PROTACs by connecting the analogues of MRTX1133 and the VHL ligand. Structural modifications of the linker moiety and KRAS inhibitor part suggested a critical role of membrane permeability in the degradation activity of the KRASG12D PROTACs. Mechanism studies with the representative compound 8o demonstrated that the potent, rapid, and selective degradation of KRASG12D induced by 8o was via a VHL- and proteasome-dependent manner. This compound selectively and potently suppressed the growth of multiple KRASG12D mutant cancer cells, displayed favorable pharmacokinetic and pharmacodynamic properties in mice, and showed significant antitumor efficacy in the AsPC-1 xenograft mouse model. Further optimization of 8o appears to be promising for the development of a new chemotherapy for KRASG12D-driven cancers as the complementary therapeutic strategy to KRAS inhibition