查看更多>>摘要：Efficient translation mediated by the 5'untranslated region(5'UTR)is essential for the robust efficacy of mRNA vaccines.However,the N1-methyl-pseudouridine(m1Ψ)modification of mRNA can impact the translation efficiency of the 5'UTR.We discovered that the optimal 5'UTR for m 1Ψ-modified mRNA(m1Ψ-5'UTR)differs significantly from its unmodified counterpart,high-lighting the need for a specialized tool for designing m1Ψ-5'UTRs rather than directly utilizing high-expression endogenous gene 5'UTRs.In response,we developed a novel machine learning-based tool,Smart5UTR,which employs a deep generative model to identify superior m1Ψ-5'UTRs in silico.The tailored loss function and network architecture enable Smart5UTR to overcome limitations inherent in existing models.As a result,Smart5UTR can successfully design superior 5'UTRs,greatly benefiting mRNA vaccine development.Notably,Smart5UTR-designed superior 5'UTRs significantly enhanced antibody titers induced by COVID-19 mRNA vaccines against the Delta and Omicron variants of SARS-CoV-2,surpassing the performance of vaccines using high-expression endogenous gene 5'UTRs.
查看更多>>摘要：In the treatment of central nervous system disease,the blood-brain barrier(BBB)is a major obstruction to drug delivery that must be overcome.In this study,we propose a brain-targeted delivery strat-egy based on selective opening of the BBB.This strategy allows some simple bare nanoparticles to enter the brain when mixed with special opening material;however,the BBB still maintains the ability to completely block molecules from passing through.Based on the screening of BBB opening and matrix delivery mate-rials,we determined that phospholipase A2-catalyzed 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphoserine li-posomes can efficiently carry drugs into the brain immediately.At an effective dose,this delivery system is safe,especially with its effect on the BBB being reversible.This mix & act delivery system has a simple structure and rapid preparation,making it a strong potential candidate for drug delivery across the BBB.
查看更多>>摘要：Lipid-coated perfluorocarbon nanodroplets(lp-NDs)hold great promise in bio-medicine as vehicles for drug delivery,molecular imaging and vaccine agents.However,their clinical utility is restricted by limited targeted accumulation,attributed to the innate immune system(ⅡS),which acts as the initial defense mechanism in humans.This study aimed to optimize lp-ND formulations to mini-mize non-specific clearance by the ⅡS.Ginsenosides(Gs),the principal components of Panax ginseng,possessing complement inhibition ability,structural similarity to cholesterol,and comparable fat solubi-lity to phospholipids,were used as promising candidate ⅡS inhibitors.Two different types of ginsenoside-based lp-NDs(Gs lp-NDs)were created,and their efficacy in reducing ⅡS recognition was examined.The Gs lp-NDs were observed to inhibit the adsorption of C3 in the protein corona(PC)and the generation of SC5b-9.Adding Gs to lp-NDs reduced complement adsorption and phagocytosis,resulting in a longer blood circulation time in vivo compared to lp-NDs that did not contain Gs.These results suggest that Gs can act as anti-complement and anti-phagocytosis adjuvants,potentially reducing non-specific clear-ance by the ⅡS and improving lifespan.
查看更多>>摘要：Small molecule drugs play a pivotal role in the arsenal of anticancer pharmacological agents.Nonetheless,their small size poses a challenge when directly visualizing their localization,distribution,mechanism of action(MOA),and target engagement at the subcellular level in real time.We propose a strategy for developing triple-functioning drug beacons that seamlessly integrate therapeutically relevant bioactivity,precise subcellular localization,and direct visualization capabilities within a single molecular entity.As a proof of concept,we have meticulously designed and constructed a boronic acid fluorescence drug beacon using coumarin-hemicyanine(CHB).Our CHB design includes three pivotal features:a boronic acid moiety that binds both adenosine triphosphate(ATP)and adenosine diphosphate(ADP),thus depleting their levels and disrupting the energy supply within mitochondria;a positively charged compo-nent that targets the drug beacon to mitochondria;and a sizeable conjugated luminophore that emits fluo-rescence,facilitating the application of structured illumination microscopy(SIM).Our study indicates the exceptional responsiveness of our proof-of-concept drug beacon to ADP and ATP,its efficacy in inhibit-ing tumor growth,and its ability to facilitate the tracking of ADP and ATP distribution around the mito-chondrial cristae.Furthermore,our investigation reveals that the micro-dynamics of CHB induce mitochondrial dysfunction by causing damage to the mitochondrial cristae and mitochondrial DNA.Alto-gether,our findings highlight the potential of SIM in conjunction with visual drug design as a potent tool for monitoring the in situ MOA of small molecule anticancer compounds.This approach represents a crucial advancement in addressing a current challenge within the field of small molecule drug discovery and validation.
查看更多>>摘要：Crocus sativus(saffron)is a globally autumn-flowering plant,and its stigmas are the most expensive spice and valuable herb medicine.Crocus specialized metabolites,crocins,are biosynthesized in distant species,Gardenia(eudicot)and Crocus(monocot),and the evolution of crocin biosynthesis remains poorly understood.With the chromosome-level Crocus genome assembly,we revealed that two rounds of lineage-specific whole genome triplication occurred,contributing important roles in the production of carotenoids and apocarotenoids.According to the kingdom-wide identification,phyloge-netic analysis,and functional assays of carotenoid cleavage dioxygenases(CCDs),we deduced that the duplication,site positive selection,and neofunctionalization of Crocus-specific CCD2 from CCD1 members are responsible for the crocin biosynthesis.In addition,site mutation of CsCCD2 revealed the key amino acids,including 1143,L146,R161,E181,T259,and S292 related to the catalytic activity of zeaxanthin cleavage.Our study provides important insights into the origin and evolution of plant special-ized metabolites,which are derived by duplication events of biosynthetic genes.
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