查看更多>>摘要：Folic acid is a fully oxidized synthetic folate with high bioavailability and stability which has been extensively prescribed to prevent congenital disabilities.Here we revealed the immunosuppressive effect of folic acid by targeting splenic marginal zone B(MZB)cells.Folic acid demonstrates avid bind-ing with the Fc domain of immunoglobulin M(IgM),targeting IgM positive MZB cells in vivo to desta-bilize IgM-B cell receptor(BCR)complex and block immune responses.The induced anergy of MZB cells by folic acid provides an immunological escaping window for antigens.Covalent conjugation of folic acid with therapeutic proteins and antibodies induces immunological evasion to mitigate the produc-tion of anti-drug antibodies,which is a major obstacle to the long-term treatment of biologics by reducing curative effects and/or causing adverse reactions.Folic acid acts as a safe and effective immunosuppres-sant via IgM-mediated MZB cells targeting to boost the clinical outcomes of biologics by inhibiting the production of anti-drug antibodies,and also holds the potential to treat other indications that adverse im-mune responses need to be transiently shut off.
查看更多>>摘要：Radiotherapy(RT)can potentially induce systemic immune responses by initiating immunogenic cell death(ICD)of tumor cells.However,RT-induced antitumor immunologic responses are sporadic and insufficient against cancer metastases.Herein,we construct multifunctional self-sufficient nanoparticles(MARS)with dual-enzyme activity(GOx and peroxidase-like)to trigger radical storms and activate the cascade-amplified systemic immune responses to suppress both local tumors and metastatic relapse.In addi-tion to limiting the Warburg effect to actualize starvation therapy,MARS catalyzes glucose to produce hydrogen peroxide(H2O2),which is then used in the Cu+-mediated Fenton-like reaction and RT sensitization.RT and chemodynamic therapy produce reactive oxygen species in the form of radical storms,which have a robust ICD impact on mobilizing the immune system.Thus,when MARS is combined with RT,potent sys-temic antitumor immunity can be generated by activating antigen-presenting cells,promoting dendritic cells maturation,increasing the infiltration of cytotoxic T lymphocytes,and reprogramming the immunosuppressive tumor microenvironment.Furthermore,the synergistic therapy of RT and MARS effectively suppresses local tumor growth,increases mouse longevity,and results in a 90％reduction in lung metastasis and postoperative recurrence.Overall,we provide a viable approach to treating cancer by inducing radical storms and activating cascade-amplified systemic immunity.
查看更多>>摘要：Conventional chemotherapy based on cytotoxic drugs is facing tough challenges recently following the advances of monoclonal antibodies and molecularly targeted drugs.It is critical to inspire new potential to remodel the value of this classical therapeutic strategy.Here,we fabricate bisphospho-nate coordination lipid nanogranules(BC-LNPs)and load paclitaxel(PTX)to boost the chemo-and immuno-therapeutic synergism of cytotoxic drugs.Alendronate in BC-LNPs@PTX,a bisphosphonate to block mevalonate metabolism,works as both the structure and drug constituent in nanogranules,where alendronate coordinated with calcium ions to form the particle core.The synergy of alendronate enhances the efficacy of paclitaxel,suppresses tumor metastasis,and alters the cytotoxic mechanism.Differing from the paclitaxel-induced apoptosis,the involvement of alendronate inhibits the mevalonate meta-bolism,changes the mitochondrial morphology,disturbs the redox homeostasis,and causes the accumulation of mitochondrial ROS and lethal lipid peroxides(LPO).These factors finally trigger the ferroptosis of tumor cells,an immunogenic cell death mode,which remodels the suppressive tumor im-mune microenvironment and synergizes with immunotherapy.Therefore,by switching paclitaxel-induced apoptosis to mevalonate metabolism-triggered ferroptosis,BC-LNPs@PTX provides new insight into the development of cytotoxic drugs and highlights the potential of metabolism regulation in cancer therapy.
查看更多>>摘要：Immune evasion has made ovarian cancer notorious for its refractory features,making the development of immunotherapy highly appealing to ovarian cancer treatment.The immune-stimulating cytokine IL-12 exhibits excellent antitumor activities.However,IL-12 can induce IFN-y release and sub-sequently upregulate PDL-1 expression on tumor cells.Therefore,the tumor-targeting folate-modified de-livery system F-DPC is constructed for concurrent delivery of IL-12 encoding gene and small molecular PDL-1 inhibitor(iPDL-1)to reduce immune escape and boost anti-tumor immunity.The physicochemical characteristics,gene transfection efficiency of the F-DPC nanoparticles in ovarian cancer cells are analyzed.The immune-modulation effects of combination therapy on different immune cells are also studied.Results show that compared with non-folate-modified vector,folate-modified F-DPC can improve the targeting of ovarian cancer and enhance the transfection efficiency of pIL-12.The underlying anti-tumor mechanisms include the regulation of T cells proliferation and activation,NK activation,macrophage polarization and DC maturation.The F-DPC/pIL-12/iPDL-1 complexes have shown outstanding antitumor effects and low toxicity in peritoneal model of ovarian cancer in mice.Taken together,our work provides new insights into ovarian cancer immunotherapy.Novel F-DPC/pIL-12/iPDL-1 complexes are revealed to exert prominent anti-tumor effect by modulating tumor immune micro-environment and preventing immune escape and might be a promising treatment option for ovarian can-cer treatment.
查看更多>>摘要：Pyran-and furanocoumarins are key representatives of tetrahydropyrans and tetrahydrofu-rans,respectively,exhibiting diverse physiological and medical bioactivities.However,the biosynthetic mechanisms for their core structures remain poorly understood.Here we combined multiomics analyses of biosynthetic enzymes in Peucedanum praeruptorum and in vitro functional verification and identified two types of key enzymes critical for pyran and furan ring biosynthesis in plants.These included three distinct P.praeruptorum prenyltransferases(PpPT1-3)responsible for the prenylation of the simple coumarin skeleton 7 into linear or angular precursors,and two novel CYP450 cyclases(PpDC and PpOC)crucial for the cyclization of the linear/angular precursors into either tetrahydropyran or tetrahydrofuran scaffolds.Biochemical analyses of cyclases indicated that acid/base-assisted epoxide ring opening contributed to the enzyme-catalyzed tetrahydropyran and tetrahydrofuran ring refactoring.The possible acid/base-assisted catalytic mechanisms of the identified cyclases were theoretically investigated and as-sessed using site-specific mutagenesis.We identified two possible acidic amino acids Glu303 in PpDC and Asp301 in PpOC as vital in the catalytic process.This study provides new enzymatic tools in the epoxide formation/epoxide-opening mediated cascade reaction and exemplifies how plants become chem-ically diverse in terms of enzyme function and catalytic process.
查看更多>>摘要：Peptides are a particular molecule class with inherent attributes of some small-molecule drugs and macromolecular biologics,thereby inspiring continuous searches for peptides with therapeutic and/or agrochemical potentials.However,the success rate is decreasing,presumably because many inter-esting but less-abundant peptides are so scarce or labile that they are likely'overlooked'during the char-acterization effort.Here,we present the biochemical characterization and druggability improvement of an unprecedented minor fungal RiPP(ribosomally synthesized and post-translationally modified peptide),named acalitide,by taking the relevant advantages of metabolomics approach and disulfide-bridged sub-structure which is more frequently imprinted in the marketed peptide drug molecules.Acalitide is biosyn-thetically unique in the macrotricyclization via two disulfide bridges and a protease(AcaB)-catalyzed lactamization of AcaA,an unprecedented precursor peptide.Such a biosynthetic logic was successfully re-edited for its sample supply renewal to facilitate the identification of the in vitro and in vivo antipar-kinsonian efficacy of acalitide which was further confirmed safe and rendered brain-targetable by the liposome encapsulation strategy.Taken together,the work updates the mining strategy and biosynthetic complexity of RiPPs to unravel an antiparkinsonian drug candidate valuable for combating Parkinson's disease that is globally prevailing in an alarming manner.
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