Spatiotemporally Controlled T-Cell Combination Therapy for Solid Tumor.

Due to multidimensional complexity of solid tumor, development of rational T-cell combinations and corresponding formulations is still challenging. Herein, a triple combination of T cells are developed with Indoleamine 2,3-dioxygenase inhibitors (IDOi) and Cyclin-dependent kinase 4/6 inhibitors (CDK4/6i). To maximize synergism, a spatiotemporally controlled T-cell engineering technology to formulate triple drugs into one cell therapeutic, is established. Specifically, a sequentially responsive core-shell nanoparticle (SRN) encapsulating IDOi and CDK4/6i is anchored onto T cells. The yielded SRN-T cells migrated into solid tumor, and achieved a 1st release of IDOi in acidic tumor microenvironment (TME). Released IDOi restored tryptophan supply in TME, which activated effector T cells and inhibited Tregs. Meanwhile, 1st released core is internalized by tumor cells and degraded by glutathione (GSH), to realize a 2nd release of CDK4/6i, which induced up-regulated expression of C-X-C motif chemokine ligand 10 (CXCL10) and C-C motif chemokine ligand 5 (CCL5), and thus significantly increased tumor infiltration of T cells. Together, with an enhanced recruitment and activation, T cells significantly suppressed tumor growth, and prolonged survival of tumor-bearing mice. This study demonstrated rationality and superiority of a tri-drug combination mediated by spatiotemporally controlled cell-engineering technology, which provides a new treatment regimen for solid tumor.

Experimental and numerical investigation of the mechanical properties and energy evolution of sandstone-concrete combined body.

Studying the mechanical properties of rock-concrete combined body is crucial to ensure the safety and stability of engineering structures. In this paper, laboratory tests and numerical simulations are used to investigate the mechanical properties of the sandstone-concrete combined body. Uniaxial compression tests and an acoustic emission monitoring system are used to analyze the failure characteristics of the sandstone-concrete sample and to validate the accuracy of the numerical model. The mechanical properties of the composite body were further analyzed by integrating energy and damage theories. The results of the sandstone-concrete study suggest that the combined sandstone-concrete body exhibits synergistic deformation and failure when subjected to uniaxial compression. The peak stress and elastic modulus fall between those of sandstone and concrete. The interface's shape causes the stress in the y-direction to transition from tensile stress to compressive stress. Energy is stored before reaching the peak stress and released after reaching the peak stress. The damage curve indicates that the damage increases gradually with the strain, and it results in plastic failure. In the numerical simulation of triaxial compression, the stress and displacement at the interface are evenly distributed. Compared to uniaxial compression, the energy of each component is higher and shows a linear positive correlation with confining pressure. Additionally, the rate of energy dissipation increases with higher confining pressure. The damage variable also increases with the increase in confining pressure, and the plastic failure process is also apparent under triaxial compression.