Non-cytotoxic nanoparticles re-educating macrophages achieving both innate and adaptive immune responses for tumor therapy

Macrophages are important antigen-presenting cells to combat tumor via both innate and adaptive immunity,while they are programmed toM2 phenotype in established tumors and instead promote cancer development and metastasis.Here,we develop a nanomedicine that can re-educate M2 polarized macrophages to restore their anti-tumor activities.The nanomedicine has a core-shell structure to co-load IPI549,a PI3Kγinhibitor,and CpG,a Toll-like receptor 9 agonist.Specifically,the hydrophobic IPI549 is self-assembled into a pure drug nano-core,while MOF shell layer is coated for CpG encapsulation,achieving extra-high total drugs loading of 44%.Such nanosystem could facilitate intracellular delivery of the payloads but without any cytotoxicity,displaying excellent biocompatibility.After entering macrophages,the released IPI549 and CpG exert a synergistic effect to switch macrophages from M2 to M1 phenotype,which enables anti-tumor activities via directly engulfing tumor cells or excreting tumor killing cytokines.Moreover,tumor antigens released from the dying tumor cells could be effectively presented by the re-educated macrophages owing to the up-regulation of various antigen presenting mediators,resulting in infiltration and activation of cytotoxic T lymphocytes.As a result,the nanosystem triggers a robust antitumor immune response in combination with PD-L1 antibody to inhibit tumor growth and metastasis.This work provides a non-cytotoxic nanomedicine to modulate tumor immune microenvironment by reprograming macrophages.

Auto-ignition of biomass synthesis gas in shock tube at elevated temperature and pressure

Ignition delay times of multi-component biomass synthesis gas(bio-syngas) diluted in argon were measured in a shock tube at elevated pressure(5, 10 and 15 bar, 1 bar = 105Pa), wide temperature ranges(1,100–1,700 K) and various equivalence ratios(0.5, 1.0, 2.0). Additionally, the effects of the variations of main constituents(H2:CO = 0.125–8) on ignition delays were investigated. The experimental results indicated that the ignition delay decreases as the pressure increases above certain temperature(around 1,200 K) and vice versa. The ignition delays were also found to rise as CO concentration increases, which is in good agreement with the literature. In addition, the ignition delays of bio-syngas were found increasing as the equivalence ratio rises. This behavior was primarily discussed in present work. Experimental results were also compared with numerical predictions of multiple chemical kinetic mechanisms and Li's mechanism was found having the best accuracy. The logarithmic ignition delays were found nonlinearly decrease with the H2 concentration under various conditions, and the effects of temperature,equivalence ratio and H2 concentration on the ignition delays are all remarkable. However, the effect of pressure is relatively smaller under current conditions. Sensitivity analysis and reaction pathway analysis of methane showed that R1(H ? O2= O ? OH) is the most sensitive reaction promoting ignition and R13(H ? O2(?M) = HO2(?M)), R53(CH3? H(?M) = CH4(?M)), R54(CH4? H =CH3? H2) as well as R56(CH4? OH = CH3? H2O) are key reactions prohibiting ignition under current experimental conditions. Among them, R53(CH3? H(?M) = CH4(?M)), R54(CH4? H = CH3? H2) have the largest positive sensitivities and the high contribution rate in rich mixture.The rate of production(ROP) of OH of R1 showed that OH ROP of R1 decreases sharply as the mixture turns rich.Therefore, the ignition delays become longer as the equivalence ratio increases.