查看更多>>摘要：Inefficient drug penetration hurdled by the stroma in the tumor tissue leads to a diminished therapeutic effect for drugs and a reduced infiltration level of immune cells.Herein,we constructed a PEGylated dendritic epirubicin(Epi)prodrug(Epi-P4D)to regulate the metabolism of cancer-associated fibroblasts(CAFs),thus enhancing Epi penetration into both multicellular tumor spheroids(MTSs)and tumor tissues in mouse colon cancer(CT26),mouse breast cancer(4T1)and human breast cancer(MDA-MB-231)models.Enhanced cytotoxicity against CT26 MTSs and remarkable antitumor efficacy of Epi-P4D were ascribed to reduced fibronectin,α-SMA,and collagen secretion.Besides,thin-ning of the tumor tissue stroma and efficient eradication of tumor cells promoted the immunogenic cell death effect for dendritic cell(DC)maturation and subsequent immune activation,including elevating the CD4+T cell population,reducing CD4+and CD8+T cell hyperactivation and exhaustion,and ampli-fying the natural killer(NK)cell proportion and effectively activating them.As a result,this dendritic nanomedicine thinned the stroma of tumor tissues to enhance drug penetration and facilitate immune cell infiltration for elevated antitumor efficacy.
查看更多>>摘要：Due to the insufficient Cu+accumulation,Cu+efflux mechanism,and highly immunosuppres-sive tumor microenvironment(TME)in lung metastasis,the cuproptosis efficacy is limited.Herein,an inhalable nanodevice(CLDCu)is constructed to successfully overcome the drawbacks of cuproptosis.CLDCu consists of a Cu2+-chitosan shell and low molecular weight heparin-tocopherol succinate(LMWH-TOS,LT)core with disulfiram(DSF)loading.The prepared CLDCu can be inhaled and accumulate in large amounts in lung lesions(63.6％)with 56.5 times higher than intravenous injection.Within tumor cells,the mild acidity triggers the co-release of DSF and Cu2+,thus generating bis(diethyldithiocarbamate)-copper(CuET)to block Cu+efflux protein ATP7B and forming toxic Cu+,leading to enhanced cuproptosis.Mean-while,the released chitosan cooperates with CLDCu-induced cuproptosis to activate stimulator of interferon genes(STING)pathway,which significantly potentiates dendritic cells(DCs)maturation,as wells as evokes innate and adaptive immunity.In lung metastatic mice model,CLDCu is found to induce cuproptosis and reverse the immunosuppressive TME by inhalation administration.Moreover,CLDCu combined with anti-programmed cell death protein ligand-1 antibody(aPD-L1)provokes stronger antitumor immunity.Therefore,nanomedicine that combines cuproptosis with STING activation is a novel strategy for tumor immunotherapy.
查看更多>>摘要：SMAD4 deficiency in colorectal cancer(CRC)is highly correlated with liver metastasis and high mortality,yet there are few effective precision therapies available.Here,we show that CCR1+-granulocytic myeloid-derived suppressor cells(G-MDSCs)are highly infiltrated in SMAD4-deficient CRC via CCL15/CCR1 and CCL9/CCR1 axis in clinical specimens and mouse models,respec-tively.The excessive TGF-β,secreted by tumor-infiltrated CCRl+-G-MDSCs,suppresses the immune response of cytotoxic T lymphocytes(CTLs),thus facilitating metastasis.Hereby,we develop engineered nanovesicles displaying CCR1 and TGFBR2 molecules(C/T-NVs)to chemotactically target the tumor driven by CCL9/CCR1 axis and trap TGF-β through TGF-β-TGFBR2 specific binding.Chemotactic C/T-NVs counteract CCR1+-G-MDSC infiltration through competitive responding CCL9/CCR1 axis.C/T-NVs-induced intratumoral TGF-β exhaustion alleviates the TGF-β-suppressed immune response of CTLs.Collectively,C/T-NVs attenuate liver metastasis of SMAD4-deficient CRC.In further exploration,high expression of programmed cell death ligand-1(PD-L1)is observed in clinical specimens of SMAD4-deficient CRC.Combining C/T-NVs with anti-PD-L1 antibody(aPD-L1)induces tertiary lymphoid structure formation with sustained activation of CTLs,CXCL13+-CD4+T,CXCR5+-CD20+B cells,and enhanced secretion of cytotoxic cytokine interleukin-21 and IFN-γ around tumors,thus eradicating metastatic foci.Our strategy elicits pleiotropic antimetastatic immunity,paving the way for nanovesicle-mediated precision immunotherapy in SMAD4-deficient CRC.
查看更多>>摘要：Dexamethasone(DEX)is used to treat ocular surface diseases.However,regulating DEX duration in tears while preventing its absorption into the anterior chamber is critical for balancing its ther-apy effects and the side effects.In this study,a novel magnetic nanoparticle(MNP)-micelle(MC)co-delivery system(MMDS)was developed.The MC moiety in the MMDS served as the carrier for DEX and the MNP part endowed the MMDS with magnetic-responsive properties.To extend its resi-dency,the MMDS was magnetically attracted by an external magnet after instilling,which acted as a precorneal drug-depot enabling a sustainable release of DEX in tears.With combination of magnet treat-ment,the topical instillation of MMDS@DEX significantly prolonged the DEX-retention in tears and increased the DEX-concentration in the cornea and conjunctiva,as well as concurrently reduced the DEX-level in the aqueous humor,when compared with the commercial DEX eye drop treatment.The combination of MMDS@DEX and magnet treatment exerted significantly better therapeutic effects against DED with smaller side effects than conventional treatments including DEX suspension,commer-cial DEX eye drops,as well as the MMDS@DEX treatment alone.The present work provided a new method for the effective delivery of DEX to ocular surface tissues while reducing its side effects,which will be beneficial to the treatments of a wide range of ocular surface diseases.
查看更多>>摘要：Glycosylation is an important post-modification reaction in plant secondary metabolism,and contributes to structural diversity of bioactive natural products.In plants,glycosylation is usually catalyzed by UDP-glycosyltransferases.Flavonoid 2'-O-glycosides are rare glycosides.However,no UGTs have been reported,thus far,to specifically catalyze 2'-O-glycosylation of flavonoids.In this work,UGT71AP2 was identified from the medicinal plant Scutellaria baicalensis as the first flavonoid 2'-O-glycosyltransferase.It could preferentially transfer a glycosyl moiety to 2'-hydroxy of at least nine flavonoids to yield six new compounds.Some of the 2'-O-glycosides showed noticeable inhibitory activities against cyclooxygenase 2.The crystal structure of UGT71AP2(2.15 A)was solved,and mechanisms of its regio-selectivity was interpreted by pAa calculations,molecular docking,MD simulation,MM/GBSA binding free energy,QM/MM,and hydrogen-deuterium exchange mass spectrometry analysis.Through structure-guided rational design,we obtained the L138T/V179D/M180T mutant with remarkably enhanced regio-selectivity(the ratio of 7-O-glycosylation byproducts decreased from 48％to 4％)and catalytic efficiency of 2'-O-glycosylation(kcat/Km,0.23 L/(s·pmol),12-fold higher than the native).Moreover,UGT71AP2 also possesses moderate UDP-dependent de-glycosylation activity,and is a dual function glycosyltransferase.This work provides an efficient bio-catalyst and sets a good example for protein engineering to optimize enzyme catalytic features through rational design.
查看更多>>摘要：Coumarins,derived from the phenylpropanoid pathway,represent one of the primary metabolites found in angiosperms.The alignment of the tetrahydropyran(THP)and tetrahydrofuran(THF)rings with the lactone structure results in the formation of at least four types of complex coumarins.However,the mechanisms underlying the structural diversity of coumarin remain poorly understood.Here,we report the chromosome-level genome assembly of Notopterygium incisum,spanning 1.64 Gb,with a contig N50 value of 22.7 Mb and 60,021 annotated protein-coding genes.Additionally,we identified the key enzymes responsible for shaping the structural diversity of coumarins,including two p-coumaroyl CoA 2'-hydroxylases crucial for simple coumarins basic skeleton architecture,two UbiA prenyltransferases responsible for angular or linear coumarins biosynthesis,and five CYP736 cyclases involved in THP and THF ring formation.Notably,two bifunctional enzymes capable of catalyzing both demethylsuberosin and osthenol were identified for the first time.Evolutionary analysis implies that tandem and ectopic duplications of the CYP736 subfamily,specifically arising in the Apiaceae,contributed to the structural diversity of coumarins in N.incisum.Conclusively,this study proposes a parallel evolution scenario for the complex coumarin biosynthetic pathway among different angiosperms and provides essential synthetic biology elements for the heterologous industrial production of coumarins.
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