Respiratory post-acute sequelae of COVID-19(PASC)persists in many SARS-CoV-2 survivors,yet no therapies specifically address its long-term pulmonary damage.We demonstrate that a single-dose clustered regularly intersp...Respiratory post-acute sequelae of COVID-19(PASC)persists in many SARS-CoV-2 survivors,yet no therapies specifically address its long-term pulmonary damage.We demonstrate that a single-dose clustered regularly interspaced short palindromic repeats(CRISPR)–CasRx nanotherapy targeting the host enzyme cathepsin L(SCNC)effectively reduces acute SARS-CoV-2 infection in Syrian hamsters,with antiviral efficacy comparable to Paxlovid.Importantly,SCNC outperforms Paxlovid in alleviating alveolar epithelial hyperplasia and lung inflammation at 31 days post-infection,a recognized PASC time point.Single-cell RNA sequencing reveals that SCNC enhances alveolar repair by promoting the differentiation of alveolar type 2 cells into alveolar type 1 cells and by reducing inflammatory infiltration through multiple signaling pathways.Thus,SCNC exerts a dual mechanism:host-directed viral inhibition and promotion of epithelial repair with reduced inflammation.This distinguishes it from therapies focused solely on viral suppression or symptom relief.These findings support SCNC as a promising therapeutic candidate for acute infection and,particularly,for PASC-related lung injury,where options remain limited.展开更多
Since the approval of the lipid nanoparticles(LNP)-mRNA vaccines against the SARS-CoV-2 virus,there has been an increased interest in the delivery of mRNA through LNPs.However,current LNP formulations contain PEG lipi...Since the approval of the lipid nanoparticles(LNP)-mRNA vaccines against the SARS-CoV-2 virus,there has been an increased interest in the delivery of mRNA through LNPs.However,current LNP formulations contain PEG lipids,which can stimulate the generation of anti-PEG antibodies.The presence of these antibodies can potentially cause adverse reactions and reduce therapeutic efficacy after administration.Given the widespread deployment of the COVID-19 vaccines,the increased exposure to PEG may necessitate the evaluation of alternative LNP formulations without PEG components.In this study,we investigated a series of polysarcosine(pSar)lipids as alternatives to the PEG lipids to determine whether pSar lipids could still provide the functionality of the PEG lipids in the ALC-0315 and SM-102 LNP systems.We found that complete replacement of the PEG lipid with a pSar lipid can increase or maintain mRNA delivery efficiency and exhibit similar safety profiles in vivo.展开更多
Activated fibroblasts are major mediators of pulmonary fibrosis.Fibroblasts are generally found in the connective tissue but upon activation can generate excess extracellular matrix(ECM)in the lung interstitial sectio...Activated fibroblasts are major mediators of pulmonary fibrosis.Fibroblasts are generally found in the connective tissue but upon activation can generate excess extracellular matrix(ECM)in the lung interstitial section.Therefore,fibroblasts are one of the most targeted cells for treating idiopathic pulmonary fibrosis(IPF).Here,we develop an anti-fibrotic platform that can modulate both the lysophosphatidic acid receptor 1(LPA_(1))and the inflammatory pathway through tumor necrosis factorα-induced protein 3(TNFAIP3,also known as A20)in fibroblasts.First,we synthesized a series of LPA_(1) antagonists,AM095 and AM966,derived amino lipids(LA lipids)which were formulated into LA-lipid nanoparticles(LA-LNPs)encapsulating mRNA.Specifically,LA5-LNPs,with AM966 head group and biodegradable acetal lipid tails,showed efficient A20 mRNA delivery to lung fibroblasts in vitro(80.2%±1.5%)and ex vivo(17.2%±0.4%).When treated to primary mouse lung fibroblasts(MLF),this formulation inhibited fibroblast migration and collagen production,thereby slowing the progression of IPF.Overall,LA5-LNPs encapsulated with A20 mRNA is a novel platform offering a potential approach to regulate fibroblast activation for the treatment of IPF.展开更多
Messenger RNA(mRNA)has drawn much attention in the medical field.Through various treatment approaches including protein replacement therapies,gene editing,and cell engineering,mRNA is becoming a potential therapeutic ...Messenger RNA(mRNA)has drawn much attention in the medical field.Through various treatment approaches including protein replacement therapies,gene editing,and cell engineering,mRNA is becoming a potential therapeutic strategy for cancers.However,delivery of mRNA into targeted organs and cells can be challenging due to the unstable nature of its naked form and the low cellular uptake.Therefore,in addition to mRNA modification,efforts have been devoted to developing nanoparticles for mRNA delivery.In this review,we introduce four categories of nanoparticle platform systems:lipid,polymer,lipid-polymer hybrid,and protein/peptide-mediated nanoparticles,together with their roles in facilitating mRNA-based cancer immunotherapies.We also highlight promising treatment regimens and their clinical translation.展开更多
Cell therapy has revolutionized the treatment of various diseases,such as cancers,genetic disorders,and autoimmune diseases.Currently,most cell therapy products rely on ex vivo cell engineering,which requires sophisti...Cell therapy has revolutionized the treatment of various diseases,such as cancers,genetic disorders,and autoimmune diseases.Currently,most cell therapy products rely on ex vivo cell engineering,which requires sophisticated manufacturing processes and poses safety concerns.The implementation of in situ cell therapy holds the potential to overcome the current limitations of cell therapy and provides a broad range of applications and clinical feasibility in the future.A variety of biomaterials have been developed to improve the function and target delivery to specific cell types due to their excellent biocompatibility,tunable properties,and other functionalities,which provide a reliable method to achieve in vivo modulation of cell reprogramming.In this article,we summarize recent advances in biomaterials for in situ cell therapy including T cells,macrophages,dendritic cells,and stem cells reprogramming leveraging lipid nanoparticles,polymers,inorganic materials,and other biomaterials.Finally,we discuss the current challenges and future perspectives of biomaterials for in situ cell therapy.展开更多
文摘Respiratory post-acute sequelae of COVID-19(PASC)persists in many SARS-CoV-2 survivors,yet no therapies specifically address its long-term pulmonary damage.We demonstrate that a single-dose clustered regularly interspaced short palindromic repeats(CRISPR)–CasRx nanotherapy targeting the host enzyme cathepsin L(SCNC)effectively reduces acute SARS-CoV-2 infection in Syrian hamsters,with antiviral efficacy comparable to Paxlovid.Importantly,SCNC outperforms Paxlovid in alleviating alveolar epithelial hyperplasia and lung inflammation at 31 days post-infection,a recognized PASC time point.Single-cell RNA sequencing reveals that SCNC enhances alveolar repair by promoting the differentiation of alveolar type 2 cells into alveolar type 1 cells and by reducing inflammatory infiltration through multiple signaling pathways.Thus,SCNC exerts a dual mechanism:host-directed viral inhibition and promotion of epithelial repair with reduced inflammation.This distinguishes it from therapies focused solely on viral suppression or symptom relief.These findings support SCNC as a promising therapeutic candidate for acute infection and,particularly,for PASC-related lung injury,where options remain limited.
文摘Since the approval of the lipid nanoparticles(LNP)-mRNA vaccines against the SARS-CoV-2 virus,there has been an increased interest in the delivery of mRNA through LNPs.However,current LNP formulations contain PEG lipids,which can stimulate the generation of anti-PEG antibodies.The presence of these antibodies can potentially cause adverse reactions and reduce therapeutic efficacy after administration.Given the widespread deployment of the COVID-19 vaccines,the increased exposure to PEG may necessitate the evaluation of alternative LNP formulations without PEG components.In this study,we investigated a series of polysarcosine(pSar)lipids as alternatives to the PEG lipids to determine whether pSar lipids could still provide the functionality of the PEG lipids in the ALC-0315 and SM-102 LNP systems.We found that complete replacement of the PEG lipid with a pSar lipid can increase or maintain mRNA delivery efficiency and exhibit similar safety profiles in vivo.
基金the Maximizing Investigators’Research Award(No.R35GM119679)the National Institute of General Medical Sciences(No.R35GM144117)+1 种基金the support from the Professor Sylvan G.Frank Graduate Fellowshipthe Presidential Fellowship.
文摘Activated fibroblasts are major mediators of pulmonary fibrosis.Fibroblasts are generally found in the connective tissue but upon activation can generate excess extracellular matrix(ECM)in the lung interstitial section.Therefore,fibroblasts are one of the most targeted cells for treating idiopathic pulmonary fibrosis(IPF).Here,we develop an anti-fibrotic platform that can modulate both the lysophosphatidic acid receptor 1(LPA_(1))and the inflammatory pathway through tumor necrosis factorα-induced protein 3(TNFAIP3,also known as A20)in fibroblasts.First,we synthesized a series of LPA_(1) antagonists,AM095 and AM966,derived amino lipids(LA lipids)which were formulated into LA-lipid nanoparticles(LA-LNPs)encapsulating mRNA.Specifically,LA5-LNPs,with AM966 head group and biodegradable acetal lipid tails,showed efficient A20 mRNA delivery to lung fibroblasts in vitro(80.2%±1.5%)and ex vivo(17.2%±0.4%).When treated to primary mouse lung fibroblasts(MLF),this formulation inhibited fibroblast migration and collagen production,thereby slowing the progression of IPF.Overall,LA5-LNPs encapsulated with A20 mRNA is a novel platform offering a potential approach to regulate fibroblast activation for the treatment of IPF.
基金support from the Maximizing Investigators'Research Awards(R35GM119679,USA)and(R35GM144117,USA)from the National Institute of General Medical Sciences。
文摘Messenger RNA(mRNA)has drawn much attention in the medical field.Through various treatment approaches including protein replacement therapies,gene editing,and cell engineering,mRNA is becoming a potential therapeutic strategy for cancers.However,delivery of mRNA into targeted organs and cells can be challenging due to the unstable nature of its naked form and the low cellular uptake.Therefore,in addition to mRNA modification,efforts have been devoted to developing nanoparticles for mRNA delivery.In this review,we introduce four categories of nanoparticle platform systems:lipid,polymer,lipid-polymer hybrid,and protein/peptide-mediated nanoparticles,together with their roles in facilitating mRNA-based cancer immunotherapies.We also highlight promising treatment regimens and their clinical translation.
基金National Institute of General Medical Sciences,Grant/Award Number:R35GM144117。
文摘Cell therapy has revolutionized the treatment of various diseases,such as cancers,genetic disorders,and autoimmune diseases.Currently,most cell therapy products rely on ex vivo cell engineering,which requires sophisticated manufacturing processes and poses safety concerns.The implementation of in situ cell therapy holds the potential to overcome the current limitations of cell therapy and provides a broad range of applications and clinical feasibility in the future.A variety of biomaterials have been developed to improve the function and target delivery to specific cell types due to their excellent biocompatibility,tunable properties,and other functionalities,which provide a reliable method to achieve in vivo modulation of cell reprogramming.In this article,we summarize recent advances in biomaterials for in situ cell therapy including T cells,macrophages,dendritic cells,and stem cells reprogramming leveraging lipid nanoparticles,polymers,inorganic materials,and other biomaterials.Finally,we discuss the current challenges and future perspectives of biomaterials for in situ cell therapy.
