mRNA is a highly promising approach for disease prevention,yet its further application is currently limited by the low efficiency of delivery.Lipid nanoparticles(LNPs)are the mainstream delivery vehicles at present,an...mRNA is a highly promising approach for disease prevention,yet its further application is currently limited by the low efficiency of delivery.Lipid nanoparticles(LNPs)are the mainstream delivery vehicles at present,and ionizable lipids,as a key component,have a particularly significant impact on delivery efficiency.To improve the efficiency of delivery,a library of ionizable lipids with tetra-branched hydrophobic tails was designed and synthesized by the Michael addition reaction.From this library,the lipid 10A was selected for the highest delivery efficiency.Further formulation screening yielded LNPs with excellent performance,which showed good efficacy in tumor prevention experiments.At the same time,the structure-activity relationship between the ionizable lipid structure and the delivery efficiency was elucidated.It was that the tetra-branched hydrophobic tails,as compared with the di-branched hydrophobic tails enhanced the stability of LNPs,provided uniformity of particle size and improved the efficiency of endocytosis and lysosomal escape,resulting in higher delivery efficiency.Meanwhile,tetra-branched lipids with hydroxyl groups in the head group performed even better.This research provides a theoretical basis and foundation for guiding the development of the next generation of ionizable lipids,and the developed 10A LNP also shows broad prospects for clinical translation.展开更多
Stem cell-based transplantation is a promising therapeutic approach for intervertebral disc degeneration(IDD).Current limitations of stem cells include with their insufficient cell source,poor proliferation capacity,l...Stem cell-based transplantation is a promising therapeutic approach for intervertebral disc degeneration(IDD).Current limitations of stem cells include with their insufficient cell source,poor proliferation capacity,low nucleus pulposus(NP)-specific differentiation potential,and inability to avoid pyroptosis caused by the acidic IDD microenvironment after transplantation.To address these challenges,embryo-derived long-term expandable nucleus pulposus progenitor cells(NPPCs)and esterase-responsive ibuprofen nano-micelles(PEG-PIB)were prepared for synergistic transplantation.In this study,we propose a biomaterial pre-modification cell strategy;the PEG-PIB were endocytosed to pre-modify the NPPCs with adaptability in harsh IDD microenvironment through inhibiting pyroptosis.The results indicated that the PEG-PIB pre-modified NPPCs exhibited inhibition of pyroptosis in vitro;their further synergistic transplantation yielded effective functional recovery,histological regeneration,and inhibition of pyroptosis during IDD regeneration.Herein,we offer a novel biomaterial pre-modification cell strategy for synergistic transplantation with promising therapeutic effects in IDD regeneration.展开更多
基金financially supported by the National Natural Science Foundation of China(No.T2293753)the National Key R&D Program of China(No.2021YFA1201200)the“Pioneer”and“Leading Goose”R&D Program of Zhejiang(No.022C03022)。
文摘mRNA is a highly promising approach for disease prevention,yet its further application is currently limited by the low efficiency of delivery.Lipid nanoparticles(LNPs)are the mainstream delivery vehicles at present,and ionizable lipids,as a key component,have a particularly significant impact on delivery efficiency.To improve the efficiency of delivery,a library of ionizable lipids with tetra-branched hydrophobic tails was designed and synthesized by the Michael addition reaction.From this library,the lipid 10A was selected for the highest delivery efficiency.Further formulation screening yielded LNPs with excellent performance,which showed good efficacy in tumor prevention experiments.At the same time,the structure-activity relationship between the ionizable lipid structure and the delivery efficiency was elucidated.It was that the tetra-branched hydrophobic tails,as compared with the di-branched hydrophobic tails enhanced the stability of LNPs,provided uniformity of particle size and improved the efficiency of endocytosis and lysosomal escape,resulting in higher delivery efficiency.Meanwhile,tetra-branched lipids with hydroxyl groups in the head group performed even better.This research provides a theoretical basis and foundation for guiding the development of the next generation of ionizable lipids,and the developed 10A LNP also shows broad prospects for clinical translation.
基金Nature Science Foundation of Zhejiang Province(Y20H060063,LY19H060005,LQ18H060003,LZ22H090003)National Natural Science Foundation of China(NO.82072465,NO.81772379,NO.81972096,NO.82172457,NO.82002327)+1 种基金China Postdoctoral Science Foundation(2017M612011)Scientific Research Fund of Zhejiang Provincial Education Department(Y201941476).
文摘Stem cell-based transplantation is a promising therapeutic approach for intervertebral disc degeneration(IDD).Current limitations of stem cells include with their insufficient cell source,poor proliferation capacity,low nucleus pulposus(NP)-specific differentiation potential,and inability to avoid pyroptosis caused by the acidic IDD microenvironment after transplantation.To address these challenges,embryo-derived long-term expandable nucleus pulposus progenitor cells(NPPCs)and esterase-responsive ibuprofen nano-micelles(PEG-PIB)were prepared for synergistic transplantation.In this study,we propose a biomaterial pre-modification cell strategy;the PEG-PIB were endocytosed to pre-modify the NPPCs with adaptability in harsh IDD microenvironment through inhibiting pyroptosis.The results indicated that the PEG-PIB pre-modified NPPCs exhibited inhibition of pyroptosis in vitro;their further synergistic transplantation yielded effective functional recovery,histological regeneration,and inhibition of pyroptosis during IDD regeneration.Herein,we offer a novel biomaterial pre-modification cell strategy for synergistic transplantation with promising therapeutic effects in IDD regeneration.
