Herein,porous poly(lactic-co-glycolic acid)(PLGA)microspheres were prepared to load icariin andmiR-23b for the treatment of metastatic lung cancer.The microspheres exhibited desirable aerodynamic diameter,high drug lo...Herein,porous poly(lactic-co-glycolic acid)(PLGA)microspheres were prepared to load icariin andmiR-23b for the treatment of metastatic lung cancer.The microspheres exhibited desirable aerodynamic diameter,high drug loading and encapsulation efficiency,as well as a favorable drug release profile,which was beneficial for the deposition and exposure of drugs in the lung tissues.The release solution from microspheres exhibited a favorable anti-proliferative effect by inducting cell apoptosis and arresting the cell cycle at G1 phase,and meanwhile inhibited the migration and invasion of cancer cells.More importantly,the microspheres could be effectively inhaled and accumulated in the lung tissues to trigger the in situ apoptosis of tumor cells and suppress metastasis,using mice bearing melanoma-metastatic lung cancer as a model.Furthermore,inhalation of themicrospheres showed favorable biocompatibility,barely causing tissue damage.Overall,porous PLGA microspheres provide a promising platform for the inhalable co-delivery of drugs and genes to obtain ideal therapeutic efficacy in lung cancer and other pulmonary diseases.展开更多
Necroptosis,a form of programmed cell death,initiates a series of biological responses and further culminates in necroinflammatory processes,consequently limiting the efficacy of cytokine antag-onists in treating infl...Necroptosis,a form of programmed cell death,initiates a series of biological responses and further culminates in necroinflammatory processes,consequently limiting the efficacy of cytokine antag-onists in treating inflammatory diseases.To address this issue,DNAzyme R3-Dz specifically targeting receptor-interacting protein kinase 3(RIP3)mRNA,a necrosome component,has been successfully developed and studied to elucidate the mechanism in cleaving its target mRNA.Then a polyamidoamine(PAMAM)derivative was constructed through the modification of nucleobase analog(termed AP)to achieve the R3-Dz delivery to macrophages.The AP/R3-Dz nanoparticles effectively downregulated the RIP3 expression,leading to subsequent decrease in the levels of reactive oxygen species(ROS)and damage-associated molecular patterns(DAMPs),ultimately inhibiting the necroinflammatory pro-cesses mediated by the NOD-like receptor family pyrin domain-containing 3(NLRP3).Finally,AP/R3-Dz nanoparticles and their combination with the NLRP3 inhibitor MCC950 suppressed the necrotic phenotype and ameliorated the disease progression in diverse models,including gouty arthritis,autoim-mune hepatitis and rheumatoid arthritis.In summary,the AP/R3-Dz nanoparticles in combination with MCC950 have been demonstrated to achieve the intervention in necroptosis and inflammation by dual disruption of the intricate feedback loop of necroinflammation and thus have promising potential in the treatment of inflammatory diseases.展开更多
Lipid nanoparticles are promising carriers for oral drug delivery.For bioactive cargos with intracellular targets,e.g.gene-editing proteins,it is essential for the cargo and carrier to remain complexed after crossing ...Lipid nanoparticles are promising carriers for oral drug delivery.For bioactive cargos with intracellular targets,e.g.gene-editing proteins,it is essential for the cargo and carrier to remain complexed after crossing the epithelial layer of intestine in order for the delivery system to transport the cargos inside targeted cells.However,limited studies have been conducted to verify the integrity of cargo/carrier nanocomplexes and their capability in facilitating cargo delivery intracellularly after the nanocomplex crossing the epithelial barrier.Herein,we used a traditional 2D transwell system and a recently developed 3D tissue engineered intestine model and demonstrated the synthetic lipid nanoparticle(carrier)and protein(cargo)nanocomplexes are able to cross the epithelial layer and deliver the protein cargo inside the underneath cells.We found that the EC16-63 LNP efficiently encapsulated the GFP-Cre recombinase,penetrated the intestinal monolayer cells in both the 2D cell culture and 3D tissue models through temporarily interrupting the tight junctions between epithelial layer.After transporting across the intestinal epithelia,the EC16-63 and GFP-Cre recombinase nanocomplexes can enter the underneath cells to induce gene recombination.These results suggest that the in vitro 3D intestinal tissue model is useful for identifying effective lipid nanoparticles for potential oral drug delivery.展开更多
基金the National Natural Science Foundation of China(32271319 and 32071267)the Science and Technology Department of Jilin Province(YDZJ202301ZYTS537 and 20240402035GH)+1 种基金the Development and Reform Commission of Jilin Province(2023C015)the“Medicine+X”cross-innovation team of Bethune Medical Department of Jilin University“Leading the Charge with Open Competition”construction project(2022JBGS04).
文摘Herein,porous poly(lactic-co-glycolic acid)(PLGA)microspheres were prepared to load icariin andmiR-23b for the treatment of metastatic lung cancer.The microspheres exhibited desirable aerodynamic diameter,high drug loading and encapsulation efficiency,as well as a favorable drug release profile,which was beneficial for the deposition and exposure of drugs in the lung tissues.The release solution from microspheres exhibited a favorable anti-proliferative effect by inducting cell apoptosis and arresting the cell cycle at G1 phase,and meanwhile inhibited the migration and invasion of cancer cells.More importantly,the microspheres could be effectively inhaled and accumulated in the lung tissues to trigger the in situ apoptosis of tumor cells and suppress metastasis,using mice bearing melanoma-metastatic lung cancer as a model.Furthermore,inhalation of themicrospheres showed favorable biocompatibility,barely causing tissue damage.Overall,porous PLGA microspheres provide a promising platform for the inhalable co-delivery of drugs and genes to obtain ideal therapeutic efficacy in lung cancer and other pulmonary diseases.
基金supported by the National Natural Science Foun-dation of China(32471315,32000897,U24A20365 and 32271319)the Science and Technology Department of Jilin Province(YDZJ202301ZYTS537,China)+2 种基金the Development and Reform Commission of Jilin Province(2023C015 and 2024C013-8,China)the Fundamental Research Funds of the Central Uni-versities,China(2024-JCXK-11)the Innovation Program for Graduate Students of Jilin University(101832020CX095,China).
文摘Necroptosis,a form of programmed cell death,initiates a series of biological responses and further culminates in necroinflammatory processes,consequently limiting the efficacy of cytokine antag-onists in treating inflammatory diseases.To address this issue,DNAzyme R3-Dz specifically targeting receptor-interacting protein kinase 3(RIP3)mRNA,a necrosome component,has been successfully developed and studied to elucidate the mechanism in cleaving its target mRNA.Then a polyamidoamine(PAMAM)derivative was constructed through the modification of nucleobase analog(termed AP)to achieve the R3-Dz delivery to macrophages.The AP/R3-Dz nanoparticles effectively downregulated the RIP3 expression,leading to subsequent decrease in the levels of reactive oxygen species(ROS)and damage-associated molecular patterns(DAMPs),ultimately inhibiting the necroinflammatory pro-cesses mediated by the NOD-like receptor family pyrin domain-containing 3(NLRP3).Finally,AP/R3-Dz nanoparticles and their combination with the NLRP3 inhibitor MCC950 suppressed the necrotic phenotype and ameliorated the disease progression in diverse models,including gouty arthritis,autoim-mune hepatitis and rheumatoid arthritis.In summary,the AP/R3-Dz nanoparticles in combination with MCC950 have been demonstrated to achieve the intervention in necroptosis and inflammation by dual disruption of the intricate feedback loop of necroinflammation and thus have promising potential in the treatment of inflammatory diseases.
基金Q.X.acknowledges the funding support by NIH Grant R01 EB027170-01D.L.K.acknowledges the funding support by NIH grant 5U19AI131126-04.
文摘Lipid nanoparticles are promising carriers for oral drug delivery.For bioactive cargos with intracellular targets,e.g.gene-editing proteins,it is essential for the cargo and carrier to remain complexed after crossing the epithelial layer of intestine in order for the delivery system to transport the cargos inside targeted cells.However,limited studies have been conducted to verify the integrity of cargo/carrier nanocomplexes and their capability in facilitating cargo delivery intracellularly after the nanocomplex crossing the epithelial barrier.Herein,we used a traditional 2D transwell system and a recently developed 3D tissue engineered intestine model and demonstrated the synthetic lipid nanoparticle(carrier)and protein(cargo)nanocomplexes are able to cross the epithelial layer and deliver the protein cargo inside the underneath cells.We found that the EC16-63 LNP efficiently encapsulated the GFP-Cre recombinase,penetrated the intestinal monolayer cells in both the 2D cell culture and 3D tissue models through temporarily interrupting the tight junctions between epithelial layer.After transporting across the intestinal epithelia,the EC16-63 and GFP-Cre recombinase nanocomplexes can enter the underneath cells to induce gene recombination.These results suggest that the in vitro 3D intestinal tissue model is useful for identifying effective lipid nanoparticles for potential oral drug delivery.
