With the emergence of multidrug resistance(MDR)in many pathogens,bacterial infections are becoming a growing threat to public health.The frightening scenario is due largely to the formation of biofilms,in which the ba...With the emergence of multidrug resistance(MDR)in many pathogens,bacterial infections are becoming a growing threat to public health.The frightening scenario is due largely to the formation of biofilms,in which the bacteria are extremely recalcitrant to the conventional antibiotic regimens.To address the emergence of MDR and biofilm-associated infections,numerous polymer-based materials have been designed and prepared recently.The subject of this perspective is the recent development of polymer-based materials that have been applied to combat multidrug-resistant pathogens,to prevent the formation of biofilms,or enhance the eradication efficacy to mature biofilms via killing biofilm-bacteria or dispersing biofilms.The advantages and shortcomings of these polymer-based materials are discussed,as well as the challenges we are facing in the clinical translation of these systems.展开更多
After repeated frustrations with amyloid beta(Aβ)-targeted clinical trials for Alzheimer’s disease(AD)in recent years,the therapeutic focus of AD has gradually shifted from Aβto tau protein.The misfolding and aggre...After repeated frustrations with amyloid beta(Aβ)-targeted clinical trials for Alzheimer’s disease(AD)in recent years,the therapeutic focus of AD has gradually shifted from Aβto tau protein.The misfolding and aggregation of tau protein into neurofibrillary tangles(NFTs)cause neuron death and synaptic dysfunction,and the deposition of NFTs is more closely related to the severity of AD than Aβplaques.Thus,it has great potential to target tau protein aggregation for AD treatment.The hexapeptide VQIVYK(known as PHF6)in tau protein has been found to play a dominant role for tau aggregation and was widely used as a model to design tau protein aggregation inhibitors.Here,inspired by natural heat shock protein(HSPs),we fabricated a self-assembly nanochaperone based on mixed-shell polymeric micelle(MSPM)as a novel tau-targeted AD therapy.With tunable phase-separated microdomains on the surface,the nanochaperone could effectively bind with PHF6 aggregates,inhibit PHF6 aggregation,block neuronal internalization of PHF6 species,thus significantly alleviating PHF6 mediated neurotoxicity.Moreover,the as-prepared nanochaperone could work with proteinase to facilitate the degradation of PHF6 aggregates.This bioinspired nanochaperone demonstrated a new way to target tau protein and provided a promising strategy for AD treatment.展开更多
Efficient intracellular delivery of protein drugs is critical for protein therapy.The combination of protein drugs with chemotherapeutics represents a promising strategy in enhancing anti-cancer effect.However,co-deli...Efficient intracellular delivery of protein drugs is critical for protein therapy.The combination of protein drugs with chemotherapeutics represents a promising strategy in enhancing anti-cancer effect.However,co-delivery systems for efficient delivery of these two kinds of drugs are still lacking because of their different properties.Herein,we show a well-designed delivery system based on dynamic covalent bond for efficient intracellular co-delivery of ribonuclease A(RNase A)and doxorubicin(DOX).Two polymers,PEG-b-P(Asp-co-AspDA)and PAE-b-P(Asp-co-AspPBA),and two 2-acetylphenylboronic acid(2-APBA)-functionalized drugs,2-APBA-RNase A and 2-APBA-DOX,self-assemble into mixed-shell nanoparticles(RNase A/DOX@MNPs)via dynamic phenylboronic acid(PBA)-catechol bond between PBA and dopamine(DA)moieties.The PBA-catechol bond endows the nanoparticles with high stability and excellent stimulus-responsive drug release behavior.Under the slight acidic environment at tumor tissue,RNase A/DOX@MNPs are positively charged,promoting their endocytosis.Upon cellular uptake into endosome,further protonation of PAE chains leads to the rupture of endosomes because of the proton sponge effect and the cleavage of PBA-catechol bond promotes the release of two drugs.In cytoplasm,the high level of GSH removed the modification of 2-APBA on drugs.The restored RNase A and DOX show a synergistic and enhanced antic-cancer effect.This system may be a promising platform for intracellular co-delivery of protein drugs and chemotherapeutics.展开更多
Bacterial biofilms present a significant challenge in treating drug-resistant infections,necessitating the development of innovative nanomedicines.In this study,we introduce triclosan-conjugated,lipase-responsive poly...Bacterial biofilms present a significant challenge in treating drug-resistant infections,necessitating the development of innovative nanomedicines.In this study,we introduce triclosan-conjugated,lipase-responsive polymeric micelles designed to exploit biofilm properties and serve as a responsive drug delivery platform.The micelles were created using an amphiphilic block polymer synthesized via ring-opening polymerization ofε-caprolactone(CL)and triclosan-containing cyclic trimethylene carbonate(MTC-Tri).Poly(ethylene glycol)(PEG-OH)acted as the macro-initiator,resulting in micelles with a PEG shell that facilitated their penetration into bacterial biofilms.An important advantage of our micelles lies in their interaction with local bacterial lipases within biofilms.These lipases triggered rapid micelle degradation,releasing triclosan in a controlled manner.This liberated triclosan effectively eliminated bacteria embedded in the biofilms.Notably,the triclosan-conjugated micelles displayed minimal toxicity to murine fibroblasts,indicating their biocompatibility and safety.This finding emphasizes the potential application of these micelles in combatting drug resistance observed in bacterial biofilms.Our triclosan-conjugated,lipase-responsive polymeric micelles exhibit promising characteristics for addressing drug resistance in bacterial biofilms.By harnessing biofilm properties and implementing a responsive drug delivery system,we seek to provide an effective solution in the fight against drug-resistant bacteria.展开更多
Amyloidosis is characterized by the deposition of fibrillar aggregates,with a specific peptide or protein as the primary component,in affected tissues or organs.Excessive proliferation and deposition of amyloid fibril...Amyloidosis is characterized by the deposition of fibrillar aggregates,with a specific peptide or protein as the primary component,in affected tissues or organs.Excessive proliferation and deposition of amyloid fibrils can cause organismal dysfunction and lethal pathological outcomes associated with amyloidosis.In this study,a nanochaperone(nChap-NA)was developed to inhibit protein misfolding and fibrillation by simulating the function of natural molecular chaperones.The nanochaperone was prepared by self-assembly of two block copolymers PEG-b-PCL and PCL-b-P(NIPAM-co-AANTA),which had a phase-separated surface consisting of hydrophobic PNIPAM microdomains with coordinative NTA(Zn)moieties and hydrophilic PEG chains.The hydrophobic interaction of the PNIPAM microdomain and the coordination of NTA(Zn)synergistically work together to effectively trap the amyloid monomer and block its fibrillation site.Insulin and human islet amyloid polypeptide(hIAPP)were used as model proteins to investigate the nanochaperone's inhibition of amyloid misfolding and fibrillation.It was proved that the nanochaperone could stabilize the natural conformation of the trapped insulin and hIAPP,and effectively inhibit their fibrillation.In vivo study demonstrated that the nanochaperone could effectively preserve the bioactivity of insulin and reduce the cytotoxicity caused by hIAPP aggregation.This study may provide a promising strategy for the prophylactic treatment of amyloidosis.展开更多
Alzheimer’s disease(AD),one of the most prevalent progressive neurodegenerative disorders,is characterized by neurological dysfunction and is closely linked to learning and memory impairment.Despite tremendous effort...Alzheimer’s disease(AD),one of the most prevalent progressive neurodegenerative disorders,is characterized by neurological dysfunction and is closely linked to learning and memory impairment.Despite tremendous effort being involved,several anti-AD drugs come into clinical trials difficult to succeed due to the complex AD pathogenesis and the blood-brain barrier(BBB).展开更多
基金financially supported by the National Natural Science Foundation of China(Nos.21620102005,51933006,and 52003184)。
文摘With the emergence of multidrug resistance(MDR)in many pathogens,bacterial infections are becoming a growing threat to public health.The frightening scenario is due largely to the formation of biofilms,in which the bacteria are extremely recalcitrant to the conventional antibiotic regimens.To address the emergence of MDR and biofilm-associated infections,numerous polymer-based materials have been designed and prepared recently.The subject of this perspective is the recent development of polymer-based materials that have been applied to combat multidrug-resistant pathogens,to prevent the formation of biofilms,or enhance the eradication efficacy to mature biofilms via killing biofilm-bacteria or dispersing biofilms.The advantages and shortcomings of these polymer-based materials are discussed,as well as the challenges we are facing in the clinical translation of these systems.
基金financially supported by the National Natural Science Foundation of China (Nos. 51933006 and 52073306)Young Elite Scientists Sponsorship Program by Tianjin (No. TJSQNTJ-2020-18)+1 种基金the Nonprofit Central Research Institute Fund of Chinese Academy of Medical Sciences (No. 2019-RC-HL-014)Wenzhou Key Laboratory of Biomaterials and Engineering (No. WIUCASSWCL21004)
文摘After repeated frustrations with amyloid beta(Aβ)-targeted clinical trials for Alzheimer’s disease(AD)in recent years,the therapeutic focus of AD has gradually shifted from Aβto tau protein.The misfolding and aggregation of tau protein into neurofibrillary tangles(NFTs)cause neuron death and synaptic dysfunction,and the deposition of NFTs is more closely related to the severity of AD than Aβplaques.Thus,it has great potential to target tau protein aggregation for AD treatment.The hexapeptide VQIVYK(known as PHF6)in tau protein has been found to play a dominant role for tau aggregation and was widely used as a model to design tau protein aggregation inhibitors.Here,inspired by natural heat shock protein(HSPs),we fabricated a self-assembly nanochaperone based on mixed-shell polymeric micelle(MSPM)as a novel tau-targeted AD therapy.With tunable phase-separated microdomains on the surface,the nanochaperone could effectively bind with PHF6 aggregates,inhibit PHF6 aggregation,block neuronal internalization of PHF6 species,thus significantly alleviating PHF6 mediated neurotoxicity.Moreover,the as-prepared nanochaperone could work with proteinase to facilitate the degradation of PHF6 aggregates.This bioinspired nanochaperone demonstrated a new way to target tau protein and provided a promising strategy for AD treatment.
基金This work was financially supported by the National Key R&D Program of China(Nos.2022YFA1205703 and 2022YFA1205702)the National Natural Science Foundation of China(Nos.51773099,51933006 and 52103183)Haihe Laboratory of Sustainable Chemical Transformations(No.YYJC202102).
文摘Efficient intracellular delivery of protein drugs is critical for protein therapy.The combination of protein drugs with chemotherapeutics represents a promising strategy in enhancing anti-cancer effect.However,co-delivery systems for efficient delivery of these two kinds of drugs are still lacking because of their different properties.Herein,we show a well-designed delivery system based on dynamic covalent bond for efficient intracellular co-delivery of ribonuclease A(RNase A)and doxorubicin(DOX).Two polymers,PEG-b-P(Asp-co-AspDA)and PAE-b-P(Asp-co-AspPBA),and two 2-acetylphenylboronic acid(2-APBA)-functionalized drugs,2-APBA-RNase A and 2-APBA-DOX,self-assemble into mixed-shell nanoparticles(RNase A/DOX@MNPs)via dynamic phenylboronic acid(PBA)-catechol bond between PBA and dopamine(DA)moieties.The PBA-catechol bond endows the nanoparticles with high stability and excellent stimulus-responsive drug release behavior.Under the slight acidic environment at tumor tissue,RNase A/DOX@MNPs are positively charged,promoting their endocytosis.Upon cellular uptake into endosome,further protonation of PAE chains leads to the rupture of endosomes because of the proton sponge effect and the cleavage of PBA-catechol bond promotes the release of two drugs.In cytoplasm,the high level of GSH removed the modification of 2-APBA on drugs.The restored RNase A and DOX show a synergistic and enhanced antic-cancer effect.This system may be a promising platform for intracellular co-delivery of protein drugs and chemotherapeutics.
基金supported by the National Natural Science Foundation of China(Nos.22275043,52203184,52293380 and 52293383)Startup Fund of Wenzhou Institute,University of Chinese Academy of Sciences(Nos.WIUCASQD2021022 and WIUCASQD2021019).
文摘Bacterial biofilms present a significant challenge in treating drug-resistant infections,necessitating the development of innovative nanomedicines.In this study,we introduce triclosan-conjugated,lipase-responsive polymeric micelles designed to exploit biofilm properties and serve as a responsive drug delivery platform.The micelles were created using an amphiphilic block polymer synthesized via ring-opening polymerization ofε-caprolactone(CL)and triclosan-containing cyclic trimethylene carbonate(MTC-Tri).Poly(ethylene glycol)(PEG-OH)acted as the macro-initiator,resulting in micelles with a PEG shell that facilitated their penetration into bacterial biofilms.An important advantage of our micelles lies in their interaction with local bacterial lipases within biofilms.These lipases triggered rapid micelle degradation,releasing triclosan in a controlled manner.This liberated triclosan effectively eliminated bacteria embedded in the biofilms.Notably,the triclosan-conjugated micelles displayed minimal toxicity to murine fibroblasts,indicating their biocompatibility and safety.This finding emphasizes the potential application of these micelles in combatting drug resistance observed in bacterial biofilms.Our triclosan-conjugated,lipase-responsive polymeric micelles exhibit promising characteristics for addressing drug resistance in bacterial biofilms.By harnessing biofilm properties and implementing a responsive drug delivery system,we seek to provide an effective solution in the fight against drug-resistant bacteria.
基金financially supported by the National Key R&D Program of China(No.2022YFA1205700)the National Natural Science Foundation of China(Nos.51933006,52293383 and 52303188)+1 种基金the Natural Science Foundation of Tianjin,China(No.23JCYBJC01780)China Postdoctoral Science Foundation Funded Project(No.2023M731786)。
文摘Amyloidosis is characterized by the deposition of fibrillar aggregates,with a specific peptide or protein as the primary component,in affected tissues or organs.Excessive proliferation and deposition of amyloid fibrils can cause organismal dysfunction and lethal pathological outcomes associated with amyloidosis.In this study,a nanochaperone(nChap-NA)was developed to inhibit protein misfolding and fibrillation by simulating the function of natural molecular chaperones.The nanochaperone was prepared by self-assembly of two block copolymers PEG-b-PCL and PCL-b-P(NIPAM-co-AANTA),which had a phase-separated surface consisting of hydrophobic PNIPAM microdomains with coordinative NTA(Zn)moieties and hydrophilic PEG chains.The hydrophobic interaction of the PNIPAM microdomain and the coordination of NTA(Zn)synergistically work together to effectively trap the amyloid monomer and block its fibrillation site.Insulin and human islet amyloid polypeptide(hIAPP)were used as model proteins to investigate the nanochaperone's inhibition of amyloid misfolding and fibrillation.It was proved that the nanochaperone could stabilize the natural conformation of the trapped insulin and hIAPP,and effectively inhibit their fibrillation.In vivo study demonstrated that the nanochaperone could effectively preserve the bioactivity of insulin and reduce the cytotoxicity caused by hIAPP aggregation.This study may provide a promising strategy for the prophylactic treatment of amyloidosis.
文摘Alzheimer’s disease(AD),one of the most prevalent progressive neurodegenerative disorders,is characterized by neurological dysfunction and is closely linked to learning and memory impairment.Despite tremendous effort being involved,several anti-AD drugs come into clinical trials difficult to succeed due to the complex AD pathogenesis and the blood-brain barrier(BBB).
