Predatory bacteriophages have evolved a vast array of depolymerases for bacteria capture and deprotection.These depolymerases are enzymes responsible for degrading diverse bacterial surface carbohydrates.They are expl...Predatory bacteriophages have evolved a vast array of depolymerases for bacteria capture and deprotection.These depolymerases are enzymes responsible for degrading diverse bacterial surface carbohydrates.They are exploited as antibiofilm agents and antimicrobial adjuvants while rarely inducing bacterial resistance,making them an invaluable asset in the era of antibiotic resistance.Numerous depolymerases have been investigated preclinically,with evidence indicating that depolymerases with appropriate dose regimens can safely and effectively combat different multidrug-resistant pathogens in animal infection models.Additionally,some formulation approaches have been developed for improved stability and activity of depolymerases.However,depolymerase formulation is limited to liquid dosage form and remains in its infancy,posing a significant hurdle to their clinical translation,compounded by challenges in their applicability and manufacturing.Future development must address these obstacles for clinical utility.Here,after unravelling the history,diversity,and therapeutic use of depolymerases,we summarized the preclinical efficacy and existing formulation findings of recombinant depolymerases.Finally,the challenges and perspectives of depolymerases as therapeutics for humans were assessed to provide insights for their further development.展开更多
Hemophagocytic lymphohistiocytosis(HLH)is a highly fatal condition with the positive feedback loop between continued immune cell activation and cytokine storm as the core mechanism to mediate multiple organ dysfunctio...Hemophagocytic lymphohistiocytosis(HLH)is a highly fatal condition with the positive feedback loop between continued immune cell activation and cytokine storm as the core mechanism to mediate multiple organ dysfunction.Inspired by macrophage membranes harbor the receptors with special high affinity for proin-flammation cytokines,lipopolysaccharide(LPS)-stimulated macrophage membrane-coated nanoparticles(LMNP)were developed to show strong sponge ability to both IFN-γand IL-6 and suppressed overactivation of macrophages by inhibiting JAK/STAT signaling pathway both in vitro and in vivo.Besides,LMNP also efficiently alleviated HLH-related symptoms including cytopenia,hepatosplenomegaly and hepatorenal dysfunction and save the life of mouse models.Furthermore,its sponge effect also worked well for five human HLH samples in vitro.Altogether,it’s firstly demonstrated that biocompatible LMNP could dampen HLH with high potential for clinical transformation,which also provided alternative insights for the treatment of other cytokine storm-mediated pathologic conditions such as COVID-19 infection and cytokine releasing syndrome during CAR-T therapy.展开更多
Chronic inflammation is critical in the onset and progression of atherosclerosis(AS).The lipopolysaccharide(LPS)level in the circulation system is elevated in AS patients and animal models,which is correlated with the...Chronic inflammation is critical in the onset and progression of atherosclerosis(AS).The lipopolysaccharide(LPS)level in the circulation system is elevated in AS patients and animal models,which is correlated with the severity of AS.Inspired by the underlying mechanism that LPS could drive the polarization of macrophages toward the M1 phenotype,aggravate inflammation,and ultimately contribute to the exacerbation of AS,LPS in the circulation system was supposed to be the therapeutic target for AS treatment.In the present study,polymyxin(PMB)covalently conjugated to PEGylated liposomes(PLPs)were formulated to adsorb LPS through specific interactions between PMB and LPS.In vitro,the experiments demonstrated that PLPs could adsorb LPS,reduce the polarization of macrophages to M1 phenotype and inhibit the formation of foam cells.In vivo,the study revealed that PLPs treatment reduced the serum levels of LPS and pro-inflammatory cytokines,decreased the proportion of M1-type macrophages in AS plaque,stabilized AS plaque,and downsized the plaque burdens in arteries,which eventually attenuated the progression of AS.Our study highlighted LPS in the circulation system as the therapeutic target for AS and provided an alternative strategy for AS treatment.展开更多
Due to the special physiological and pathological characteristics of gliomas,most therapeutic drugs are prevented from entering the brain.To improve the poor prognosis of existing therapies,researchers have been conti...Due to the special physiological and pathological characteristics of gliomas,most therapeutic drugs are prevented from entering the brain.To improve the poor prognosis of existing therapies,researchers have been continuously developing non-invasive methods to overcome barriers to gliomas therapy.Although these strategies can be used clinically to overcome the blood-brain barrier(BBB),the accurate delivery of drugs to the glioma lesions cannot be ensured.Nano-drug delivery systems(NDDS)have been widely used for precise drug delivery.In recent years,researchers have gathered their wisdom to overcome barriers,so many well-designed NDDS have performed prominently in preclinical studies.These meticulous designs mainly include cascade passing through BBB and targeting to glioma lesions,drug release in response to the glioma microenvironment,biomimetic delivery systems based on endogenous cells/extracellular vesicles/protein,and carriers created according to the active ingredients of traditional Chinese medicines.We reviewed these well-designed NDDS in detail.Furthermore,we discussed the current ongoing and completed clinical trials of NDDS for gliomas therapy,and analyzed the challenges and trends faced by clinical translation of these well-designed NDDS.展开更多
Anti virulence strategy has been considered as one of the most promising approaches to combat drug-rcesistant bacterial infections.Porc-forming toxins(PFTs)are the largest class of bacterial toxins,inficting their vir...Anti virulence strategy has been considered as one of the most promising approaches to combat drug-rcesistant bacterial infections.Porc-forming toxins(PFTs)are the largest class of bacterial toxins,inficting their virulence ffect through creating pores on the cell membrane.However,curent solutions for eliminating PFTs are mostly designed based on their molecular structure,requiring customized design for different interactions.In the present study,we employed erythroliposome(denoted as RM-PL),a biomimetic platform constructed by artificial lipid membranes and natural erythrocyle membranes,to necutralize different hemolytic PFTs regardless of their molecular structure.When tested with model PFTs,including a-hemolysin,listeriolysin O,and streptolysin O,RM-PL could completely inhibit toxin-induced hemolysis in a concentration-dependent manner.In vivo studies further confirmed that RM-PL.could eficiently neuralize various toxins and save animals'lives without causing damage to 0rgans or tissues.In addition,we explored the underlying mechanisms of this efficient detoxification ability and found that it was mainly macrophages in the spleen and the liver that took up RM-PL-absorbed toxins through a variety of endocytosis pathways and digested them in lysosomes.In summary,the biomimetic RM-PL presented a promising system for broad-spectrum and powerful toxin neutralization with a mech-anism of lysosome-mediaed loxin degradation.展开更多
Uncontrollable hemorrhage remains staple trouble in surgical procedures and a leading cause after major trauma.The bleeding issue may trigger various pathologic scenarios that can lead to tissue morbidities and mortal...Uncontrollable hemorrhage remains staple trouble in surgical procedures and a leading cause after major trauma.The bleeding issue may trigger various pathologic scenarios that can lead to tissue morbidities and mortalities,and currently available on-site hemostatic agents are confined to a narrow therapeutic index and may carry the risk of immunogenicity.Inspired by the crucial role of platelets in the process of thrombus,a platelet-mimetic plateletsome with wound targeting and blood coagulation properties is developed for hemorrhage control.Plateletsome is formulated by integrating platelet membranes with functionalized synthetic liposomes and exhibits superior wound targeting and effective hemostasis properties.It presents less blood loss and shorter hemostasis time than the platelet membrane vehicles or the conventional liposomes in the mouse tail transection model.The strong homing of the biomimetic plateletsome to the thrombus was also confirmed,demonstrating the potential of this engineered cell membrane vesicle as a biomimetic hemostat for bleeding treatment.展开更多
基金This work was supported by the University Grants Committee,Hong Kong SAR Government(No.14112921,China).The support of HKPFS from the University Grants Committee to HonglanWang was greatly acknowledged.
文摘Predatory bacteriophages have evolved a vast array of depolymerases for bacteria capture and deprotection.These depolymerases are enzymes responsible for degrading diverse bacterial surface carbohydrates.They are exploited as antibiofilm agents and antimicrobial adjuvants while rarely inducing bacterial resistance,making them an invaluable asset in the era of antibiotic resistance.Numerous depolymerases have been investigated preclinically,with evidence indicating that depolymerases with appropriate dose regimens can safely and effectively combat different multidrug-resistant pathogens in animal infection models.Additionally,some formulation approaches have been developed for improved stability and activity of depolymerases.However,depolymerase formulation is limited to liquid dosage form and remains in its infancy,posing a significant hurdle to their clinical translation,compounded by challenges in their applicability and manufacturing.Future development must address these obstacles for clinical utility.Here,after unravelling the history,diversity,and therapeutic use of depolymerases,we summarized the preclinical efficacy and existing formulation findings of recombinant depolymerases.Finally,the challenges and perspectives of depolymerases as therapeutics for humans were assessed to provide insights for their further development.
基金National Natural Science Foundation of China(82070228,81773283)National Key R&D Program of China(No.2019YFC1316204)。
文摘Hemophagocytic lymphohistiocytosis(HLH)is a highly fatal condition with the positive feedback loop between continued immune cell activation and cytokine storm as the core mechanism to mediate multiple organ dysfunction.Inspired by macrophage membranes harbor the receptors with special high affinity for proin-flammation cytokines,lipopolysaccharide(LPS)-stimulated macrophage membrane-coated nanoparticles(LMNP)were developed to show strong sponge ability to both IFN-γand IL-6 and suppressed overactivation of macrophages by inhibiting JAK/STAT signaling pathway both in vitro and in vivo.Besides,LMNP also efficiently alleviated HLH-related symptoms including cytopenia,hepatosplenomegaly and hepatorenal dysfunction and save the life of mouse models.Furthermore,its sponge effect also worked well for five human HLH samples in vitro.Altogether,it’s firstly demonstrated that biocompatible LMNP could dampen HLH with high potential for clinical transformation,which also provided alternative insights for the treatment of other cytokine storm-mediated pathologic conditions such as COVID-19 infection and cytokine releasing syndrome during CAR-T therapy.
基金supported by the National Natural Science Foundation of China(82070228,81773283)the National Key R&D Program of China(No.2019YFC1316204)。
文摘Chronic inflammation is critical in the onset and progression of atherosclerosis(AS).The lipopolysaccharide(LPS)level in the circulation system is elevated in AS patients and animal models,which is correlated with the severity of AS.Inspired by the underlying mechanism that LPS could drive the polarization of macrophages toward the M1 phenotype,aggravate inflammation,and ultimately contribute to the exacerbation of AS,LPS in the circulation system was supposed to be the therapeutic target for AS treatment.In the present study,polymyxin(PMB)covalently conjugated to PEGylated liposomes(PLPs)were formulated to adsorb LPS through specific interactions between PMB and LPS.In vitro,the experiments demonstrated that PLPs could adsorb LPS,reduce the polarization of macrophages to M1 phenotype and inhibit the formation of foam cells.In vivo,the study revealed that PLPs treatment reduced the serum levels of LPS and pro-inflammatory cytokines,decreased the proportion of M1-type macrophages in AS plaque,stabilized AS plaque,and downsized the plaque burdens in arteries,which eventually attenuated the progression of AS.Our study highlighted LPS in the circulation system as the therapeutic target for AS and provided an alternative strategy for AS treatment.
基金financial support from National Natural Science Foundation of China(Nos.81903557 and 82074024)Natural Science Foundation of Jiangsu Province(No.BK20190802,China)+3 种基金Natural Science Foundation Youth Project of Nanjing University of Chinese Medicine(No.NZY81903557,China)the Open Project of Chinese Materia Medica First-Class Discipline of Nanjing University of Chinese Medicine(No.2020YLXK019,China)the Natural Science Foundation of the Jiangsu Higher Education Institutions of China(No.19KJB350003,China)College Students’Innovative Entrepreneurial Training Plan Program of Nanjing University of Chinese Medicine(No.202010315XJ040,China)。
文摘Due to the special physiological and pathological characteristics of gliomas,most therapeutic drugs are prevented from entering the brain.To improve the poor prognosis of existing therapies,researchers have been continuously developing non-invasive methods to overcome barriers to gliomas therapy.Although these strategies can be used clinically to overcome the blood-brain barrier(BBB),the accurate delivery of drugs to the glioma lesions cannot be ensured.Nano-drug delivery systems(NDDS)have been widely used for precise drug delivery.In recent years,researchers have gathered their wisdom to overcome barriers,so many well-designed NDDS have performed prominently in preclinical studies.These meticulous designs mainly include cascade passing through BBB and targeting to glioma lesions,drug release in response to the glioma microenvironment,biomimetic delivery systems based on endogenous cells/extracellular vesicles/protein,and carriers created according to the active ingredients of traditional Chinese medicines.We reviewed these well-designed NDDS in detail.Furthermore,we discussed the current ongoing and completed clinical trials of NDDS for gliomas therapy,and analyzed the challenges and trends faced by clinical translation of these well-designed NDDS.
基金supported by the National Natural Science Foundation of China(81773283).
文摘Anti virulence strategy has been considered as one of the most promising approaches to combat drug-rcesistant bacterial infections.Porc-forming toxins(PFTs)are the largest class of bacterial toxins,inficting their virulence ffect through creating pores on the cell membrane.However,curent solutions for eliminating PFTs are mostly designed based on their molecular structure,requiring customized design for different interactions.In the present study,we employed erythroliposome(denoted as RM-PL),a biomimetic platform constructed by artificial lipid membranes and natural erythrocyle membranes,to necutralize different hemolytic PFTs regardless of their molecular structure.When tested with model PFTs,including a-hemolysin,listeriolysin O,and streptolysin O,RM-PL could completely inhibit toxin-induced hemolysis in a concentration-dependent manner.In vivo studies further confirmed that RM-PL.could eficiently neuralize various toxins and save animals'lives without causing damage to 0rgans or tissues.In addition,we explored the underlying mechanisms of this efficient detoxification ability and found that it was mainly macrophages in the spleen and the liver that took up RM-PL-absorbed toxins through a variety of endocytosis pathways and digested them in lysosomes.In summary,the biomimetic RM-PL presented a promising system for broad-spectrum and powerful toxin neutralization with a mech-anism of lysosome-mediaed loxin degradation.
基金the National Natural Science Foundation of China(Nos.81773283,82070228)the National Key R&D Program of China(No.2019YFC1316204)。
文摘Uncontrollable hemorrhage remains staple trouble in surgical procedures and a leading cause after major trauma.The bleeding issue may trigger various pathologic scenarios that can lead to tissue morbidities and mortalities,and currently available on-site hemostatic agents are confined to a narrow therapeutic index and may carry the risk of immunogenicity.Inspired by the crucial role of platelets in the process of thrombus,a platelet-mimetic plateletsome with wound targeting and blood coagulation properties is developed for hemorrhage control.Plateletsome is formulated by integrating platelet membranes with functionalized synthetic liposomes and exhibits superior wound targeting and effective hemostasis properties.It presents less blood loss and shorter hemostasis time than the platelet membrane vehicles or the conventional liposomes in the mouse tail transection model.The strong homing of the biomimetic plateletsome to the thrombus was also confirmed,demonstrating the potential of this engineered cell membrane vesicle as a biomimetic hemostat for bleeding treatment.
