Development of a bacteria-nanosapper for the active delivery of ZIF-8 particles containing therapeutic genes for cancer immune therapy

Specific tumor-targeted gene delivery remains an unsolved therapeutic issue due to aberrant vascularization in tumor microenvironment(TME).Some bacteria exhibit spontaneous chemotaxis to-ward the anaerobic and immune-suppressive TME,which makes them ideal natural vehicles for cancer gene therapy.Here,we conjugated ZIF-8 metal-organic frameworks encapsulating eukaryotic murine interleukin 2(Il2)expression plasmid onto the surface of VNP20009,an attenuated Salmonella typhimur-ium strain with well-documented anti-cancer activity,and constructed a TME-targeted Il2 delivery system named Il2/ZIF-8@Salmonella.Both in vitro and in vivo experiments demonstrated that Il2/ZIF-8@Sal-monella maintained the tumor-targeting feature of bacteria,and could be effectively phagocytosed by in-tratumoral macrophages,thus leading to the expression and secretion of IL2 in TME.The detailed analysis of tumor immune microenvironment(TIME)showed that one dose of combinatorial Il2/ZIF-8@Salmonella achieved synergistic actions on a potent remodeling of TIME,marked by the activation of cytotoxic T cells and M1-polarization of macrophages in TME,thus leading to significant anti-tumor effects in melanoma,orthotopic hepatocellular carcinoma,and pulmonary metastasis models.More importantly,Il2/ZIF-8@Salmonella exhibited high safety to major organs and hematopoietic systems.Taken together,we report a novel plasmid/ZIF-8@Salmonella system that simultaneously achieves effec-tive TME-targeted delivery of therapeutic gene,as well as synergistic re-activation of TIME.

Simulating the GRF of Humanoid Robot Vertical Jumping Using a Simplified Model with a Foot Structure for Foot Design

There are many theories and tools for human or robot motion simulation,but most of them require complex calculations.The LNZN model(a simplified model named by the proposers)simplifies the human model and facilitates simulation of the Ground Reaction Force(GRF)of body landing by spring damping model and ignoring joint rotation movements,which can reduce the amount of computation obviously.In this paper,the LNZN model of human running is selected as the basis and is modified to obtain the LNZN model of a robot,which expands the application of the LNZN model.According to the structure of the human foot,a foot structure is then added to the simplified model to reduce the GRF.We also applied driving forces to the new model to simulate the whole high jump motion of the robot to expand the functions of the LNZN model.The obtained GRF data were anastomotic to the actual experimental results.In addition,the effects of variables,such as the mass,hardness,and damping,of the foot on the GRF at the moment of landing were also explored.Finally,based on the guidelines obtained for the design of the robot’s foot structure,we fabricated new robot’s feet and installed them on the actual robot and achieved a better cushioning effect than the original foot in experiments.