Planktonic bacteria adhere and subsequently form biofilms on implantable medical devices can cause severe infections that have become the major types of hospital-acquired infections.Traditional coatings for the implan...Planktonic bacteria adhere and subsequently form biofilms on implantable medical devices can cause severe infections that have become the major types of hospital-acquired infections.Traditional coatings for the implants are frequently lack of long-term antifouling and bactericidal activities.It is still a big challenge to simultaneously improve the antifouling and bactericidal activities of the coatings.Herein,we report that mixed-charge glycopolypeptide coatings are of long-term antibacterial activities to efficiently inhibit the biofilm growth.The glycosylation of mixed-charge polypeptides has led to a significant improvement of both antifouling and bactericidal activities.The cooperative effect of the saccharide residues and mixed-charge residues improved the resistance of the polypeptide coatings against protein adsorption.The saccharide and L-glutamic acid(E)residues collectively enhanced the bacterial membrane-disruption of cationic L-lysine(K)residues,leading to potent bactericidal activity.Meanwhile,the glycopolypeptide coatings showed superior biocompatibility,long-term antibiofilm and anti-infection properties in two types of mouse subcutaneous infection models and one type of mouse urinary tract infection model.This work provides a new strategy to achieve antibacterial coatings with long-term activities for preventing implantable medical device associated infections.展开更多
Immunotherapy has recently emerged as a promising therapeutic modality for the treatment of various diseases such as cancer,inflammation,autoimmune diseases,and infectious diseases.Despite its potential,immunotherapy ...Immunotherapy has recently emerged as a promising therapeutic modality for the treatment of various diseases such as cancer,inflammation,autoimmune diseases,and infectious diseases.Despite its potential,immunotherapy faces challenges related to delivery efficiency and off-target toxicity of immunotherapeutic drugs.Nano drug delivery systems offer improvements in drug biodistribution and release kinetics but still suffer from shortcomings such as high immunogenicity,poor penetration across biological barriers,and insufficient tissue permeability.Targeted delivery of drugs using living cells has become an emerging strategy that can take advantage of the inherent characteristics of cells to deal with the delivery defects of nano delivery systems.Furthermore,cells themselves can be genetically engineered into cellular drugs for enhanced immunotherapy.This review provides an in-depth exploration of cell-derived drug carriers,detailing their biological properties,functions,and commonly used drug loading strategies.In addition,the role of genetically modified cells in immunotherapy and their synergistic therapeutic effects with drug delivery are also introduced.By summarizing the main advancements and limitations in the field,this review offers insights into the potential of cell-based drug delivery systems to address the existing challenges in immunotherapy.The introduction to recent developments and evaluation of ongoing research will pave the way for the optimization and widespread adoption of nano/genetically engineered cells for immunotherapy.展开更多
Intracellular protein delivery is critical to the development of protein-based biopharmaceuticals and therapies.However,current delivery vectors often suffer from complicated syntheses,low generality among various pro...Intracellular protein delivery is critical to the development of protein-based biopharmaceuticals and therapies.However,current delivery vectors often suffer from complicated syntheses,low generality among various proteins,and insufficient serum stability.Herein,we developed an enlightened cytosolic protein delivery strategy by dynamically crosslinking epigallocatechin gallate(EGCG),low-molecular-weight polyethylenimine(PEI 1.8k),and 2-acetylphenylboric acid(2-APBA)on the protein surface,hence forming the EPP-protein nanocapsules(NCs).EGCG enhanced protein encapsulation via hydrogen bonding,and reduced the positive charge density of PEI to endow the NCs with high serum tolerance,thereby enabling effective cellular internalization in serum.The formation of reversible imine and boronate ester among 2-APBA,EGCG,and PEI 1.8k allowed acid-triggered dissociation of EPP-protein NCs in the endolysosomes,which triggered efficient intracellular release of the native proteins.Such strategy therefore showed high efficiency and universality for diversities of proteins with different molecular weights and isoelectric points,including enzyme,toxin,antibody,and CRISPR(clustered regularly interspaced short palindromic repeats)-Cas9 ribonucleoprotein(RNP),outperforming the commercial protein transduction reagent PULSin and RNP transfection reagent lipofectamine CMAX.Moreover,intravenously(i.v.)injected EPP-saporin NCs efficiently delivered saporin into 4T1 tumor cells to provoke robust antitumor effect.This simple,versatile,and robust cytosolic protein delivery system holds translational potentials for the development of protein-based therapeutics.展开更多
Polymeric micelles have demonstrated wide utility for chemodrug delivery,which however,still suffer from shortcomings such as undesired drug loading,disassembly upon dilution,pre-leakage of drug cargoes during systemi...Polymeric micelles have demonstrated wide utility for chemodrug delivery,which however,still suffer from shortcomings such as undesired drug loading,disassembly upon dilution,pre-leakage of drug cargoes during systemic circulation,and lack of cancer-selective drug release.Herein,a poly(ethylene glycol)(PEG)-polyphosphoester-based,reactive oxygen species (ROS)-responsive,core-cross-linked (CCL) micellar system was developed to encapsulate both chemodrug (doxorubicin,Dox) and photosensitizer (chlorin e6,Ce6).The hydrophobic core of the micelles was cross-linked via a thioketal (TK)-containing linker,which notably enhanced the drug loading and micelle stability.In tumor cells,far-red light irradiation of Ce6 generated ROS to cleave the TK linkers and disrupt the micelle cores.As such,micelles were destabilized and Dox release was promoted,which thereafter imparted synergistic anti-cancer effect with ROS-mediated photodynamic therapy.This study provides an effective approach to realize the precise control over drug loading,formulation stability,and cancer-selective drug release using polymeric micelles,and would render promising utilities for the programmed anti-cancer combination therapy.展开更多
Biomedical polymers have been extensively developed for promising applications in a lot of biomedical fields, such as therapeutic medicine delivery, disease detection and diagnosis, biosensing, regenerative medicine, ...Biomedical polymers have been extensively developed for promising applications in a lot of biomedical fields, such as therapeutic medicine delivery, disease detection and diagnosis, biosensing, regenerative medicine, and disease treatment. In this review, we summarize the most recent advances in the synthesis and application of biomedical polymers, and discuss the comprehensive understanding of their property-function relationship for corresponding biomedical applications. In particular, a few burgeoning bioactive polymers, such as peptide/biomembrane/microorganism/cell-based biomedical polymers, are also introduced and highlighted as the emerging biomaterials for cancer precision therapy. Furthermore, the foreseeable challenges and outlook of the development of more efficient, healthier and safer biomedical polymers are discussed. We wish this systemic and comprehensive review on highlighting frontier progress of biomedical polymers could inspire and promote new breakthrough in fundamental research and clinical translation.展开更多
Co-delivery of anti-inflammatory siRNA and hydrophilic drug provides a promising approach for the treatment of ulcerative colitis (UC). However, lack of a suitable and efficient co-delivery carrier poses critical chal...Co-delivery of anti-inflammatory siRNA and hydrophilic drug provides a promising approach for the treatment of ulcerative colitis (UC). However, lack of a suitable and efficient co-delivery carrier poses critical challenge against their utilization. We herein developed macrophage-targeting, reversibly crossli nked polymersomes (TKPR-RCP) based on the TKPR-modified, poly(ethyle ne glycol)-b-poly(trimethylene carbonate-codithiolane trimethylene carbonate)-b-polyethylenimine (PEG-P(TMC-DTC)-PEI) triblock copolymer, which could efficiently encapsulate TNF-α siRNA and dexamethasone sodium phosphate (DSP) in their hydrophilic core. The cationic PEI segments provided additional electrostatic interactions with cargo molecules to promote the encapsulatiion, and disulfide crosslinking of the polymersome membrane endowed the TKPR-RCP with high colloidal stability. Because the cationic PEI was embedded in the hydrophilic core, the polymersomes displayed neutral surface charge and thus possessed high serum stability. The TKPR-RCP co-encapsulating TNF-α siRNA and DSP could be efficiently internalized by macrophages (~98%) and undergo redox-responsive membrane de-crosslinking to accelerate cargo release in the cytoplasm, thus inducing efficient gene silencing and anti-inflammatory effect .Intravenous injectio n of the co-delivery TKPR-RCP mediated pote nt and cooperative anti-inflammatory effect in inflamed colons of UC mice, and significantly prevented animals from colonic injury. This study therefore provides a promising approach for the co-delivery of hydrophilic drug/siRNA toward the treatment of inflammatory bowel diseases.展开更多
Insufficient intratumoral penetration greatly hurdles the anticancer performance of nanomedicine. To realize highly efficient tumor penetration in a precisely and spatiotemporally controlled manner, far-red light-resp...Insufficient intratumoral penetration greatly hurdles the anticancer performance of nanomedicine. To realize highly efficient tumor penetration in a precisely and spatiotemporally controlled manner, far-red light-responsive nanoclusters (NCs) capable of size shrinkage and charge conversion were developed and co-administered with iRGD to synergistically improve the intratumoral penetration and the anticancer efficacy. The NCs were constructed using the singlet oxygen-sensitive (SOS) polyethylene glycolpolyurethane-polyethylene glycol (PEG-(1O2)PU-PEG) triblock copolymer to encapsulate the doxorubicin (DOX)-loaded, chlorin e6 (Ce6)-conjugated polyamindoamine (PAMAM) dendrimer (DCD) via the double-emulsion method. Co-administration of iRGD notably increased the permeability of NCs within tumor vasculature and tumor tissues. In addition, upon far-red light irradiation (660 nm) of tumors at low optical density (10 mW/cm2), the generated 1O2 could disintegrate the NCs and release the DCD with positive surface charge and ultra-small size (~ 5 nm), which synergized with iRGD to enable deep intratumoral penetration. Consequently, the local 1O2 at lethal concentrations along with the released DOX efficiently and cooperatively eradicated tumor cells. This study provides a convenient approach to spatiotemporally promote the intratumoral penetration of nanomedicine and mediate programmed anticancer therapy.展开更多
Ischemia-reperfusion (IR) injury represents a major cause of myocardial dysfunction after infarction and thrombolytic therapy, and it is closely related to the free radical explosion and overwhelming inflammatory resp...Ischemia-reperfusion (IR) injury represents a major cause of myocardial dysfunction after infarction and thrombolytic therapy, and it is closely related to the free radical explosion and overwhelming inflammatory responses. Herein, macrophage-targeting nanocomplexes (NCs) are developed to mediate efficient co-delivery of siRNA against MOF (siMOF) and microRNA-21 (miR21) into myocardial macrophages, cooperatively orches-trating the myocardial microenvironment against IR injury. Bioreducible, branched poly(β-amino ester) (BPAE-SS) is designed to co-condense siMOF and miR21 into NCs in a multivalency-reinforced approach, and they are surface-decorated with carboxylated mannan (Man-COOH) to shield the positive surface charges and enhance the serum stability. The final MBSsm NCs are efficiently internalized by myocardial macrophages after systemic administration, wherein BPAE-SS is degraded into small segments by intracellular glutathione to promote the siMOF/miR21 release, finally provoking efficient gene silencing. Thus, cardiomyocyte protection and macro-phage modulation are realized via the combined effects of ROS scavenging, inflammation inhibition, and autophagy attenuation, which ameliorates the myocardial microenvironment and restores the cardiac function via positive cellular crosstalk. This study renders promising solutions to address the multiple systemic barriers against in vivo nucleic acid delivery, and it also offers new options for IR injury by manipulating multiple reciprocal bio-reactions.展开更多
Myocardial ischemia reperfusion(IR)injury is closely related to the overwhelming inflammation in the myocardium.Herein,cardiomyocyte-targeted nanotherapeutics were developed for the reactive oxygen species(ROS)-ultras...Myocardial ischemia reperfusion(IR)injury is closely related to the overwhelming inflammation in the myocardium.Herein,cardiomyocyte-targeted nanotherapeutics were developed for the reactive oxygen species(ROS)-ultrasensitive co-delivery of dexamethasone(Dex)and RAGE small interfering RNA(siRAGE)to attenuate myocardial inflammation.PPTP,a ROSdegradable polycation based on PGE2-modified,PEGylated,ditellurium-crosslinked polyethylenimine(PEI)was developed to surface-decorate the Dex-encapsulated mesoporous silica nanoparticles(MSNs),which simultaneously condensed siRAGE and gated the MSNs to prevent the Dex pre-leakage.Upon intravenous injection to IR-injured rats,the nanotherapeutics could be efficiently transported into the inflamed cardiomyocytes via PGE2-assisted recognition of over-expressed E-series of prostaglandin(EP)receptors on the cell membranes.Intracellularly,the over-produced ROS degraded PPTP into small segments,promoting the release of siRAGE and Dex to mediate effective RAGE silencing(72%)and cooperative antiinflammatory effect.As a consequence,the nanotherapeutics notably suppressed the myocardial fibrosis and apoptosis,ultimately recovering the systolic function.Therefore,the current nanotherapeutics represent an effective example for the codelivery and on-demand release of nucleic acid and chemodrug payloads,and might find promising utilities toward the synergistic management of myocardial inflammation.展开更多
While the accelerated polymerization of N-carboxyanhydrides (NCAs) has been utilized to synthesize versatile polypeptide materials in an efficient manner with minimized side reactions, the preparation of polypeptide-b...While the accelerated polymerization of N-carboxyanhydrides (NCAs) has been utilized to synthesize versatile polypeptide materials in an efficient manner with minimized side reactions, the preparation of polypeptide-based inorganic/organic hybrid materials with the acceleration strategy remained largely unexplored. Herein, we report the accelerated ring-opening polymerization (ROP) of NCAs mediated by amine-modified inorganic nano-initiators, such as mesoporous silica nanoparticles (MSN-NH2), which is driven by the cooperative effect of the neighboring α-helical polypeptide chains in a dichloromethane (DCM)/water biphasic system. Well-defined nano-hybrids were prepared within 15 min from non-purified NCA monomers, through in situ purification and subsequent ultrafast polymerization process. NCAs can be rapidly initiated by amino groups of MSN uniformly dispersed at the interface of DCM and water, and subsequently formed the well-defined polypeptides within 15 min. The prepared inorganic/organic nano-hybrid with MSN as the core and polypeptide as the shell adopted spherical morphology and uniform size distribution due to the excellent controllability of ROP. Besides, this system is also suitable for a variety of NCAs and inorganic nano-initiators. This research allows efficient and rapid preparation of inorganic/organic nano-hybrids, and further promotes the extensive application of this material in the biomedical fields.展开更多
MicroRNA-208a(miR-208a)plays critical roles in the severe fibrosis and heart failure post myocardial ischemia/reperfusion(IR)injury.MiR-208a inhibitor(mI)with complementary RNA sequence can silence the expression of m...MicroRNA-208a(miR-208a)plays critical roles in the severe fibrosis and heart failure post myocardial ischemia/reperfusion(IR)injury.MiR-208a inhibitor(mI)with complementary RNA sequence can silence the expression of miR-208a,while it is challenging to achieve efficient and myocardium-targeted delivery.Herein,biomimetic nanocomplexes(NCs)reversibly coated with red blood cell membrane(RM)were developed for the myocardial delivery of mI.To construct the NCs,membrane-penetrating helical polypeptide(PG)was first adopted to condense mI and form the cationic inner core,which subsequently adsorbed catalase(CAT)via electrostatic interaction followed by surface coating with RM.The membrane-coated NCs enabled prolonged blood circulation after systemic administration,and could accumulate in the injured myocardium via passive targeting.In the oxidative microenvironment of injured myocardium,CAT decomposed H_(2)O_(2)to produce O_(2)bubbles,which drove the shedding of the outer RM to expose the positively charged inner core,thus facilitated effective internalization by cardiac cells.Based on the combined contribution of mI-mediated miR-208a silencing and CAT-mediated alleviation of oxidative stress,NCs effectively ameliorated the myocardial microenvironment,hence reducing the infarct size as well as fibrosis and promoting recovery of cardiac functions.This study provides an effective strategy for the cytosolic delivery of nucleic acid cargoes in the myocardium,and it renders an enlightened approach to resolve the blood circulation/cell internalization dilemma of cell membrane-coated delivery systems.展开更多
Intracellular protein therapeutics holds great potentials for the treatment of glioblastoma, which however, is greatly challenged by the unmet demands to concomitantly penetrate the blood-brain barrier(BBB) and gliobl...Intracellular protein therapeutics holds great potentials for the treatment of glioblastoma, which however, is greatly challenged by the unmet demands to concomitantly penetrate the blood-brain barrier(BBB) and glioblastoma cell membrane barrier with high efficiency and selectivity. Herein, a unique pro-protein platform was developed via facile green synthesis, which allowed efficient and selective delivery into glioblastoma cells in a carrier-free manner. Pro-proteins were engineered via reversible modification of native proteins in the aqueous buffer with 3,4-dihydroxy-phenylalanine, the substrate of L-type amino acid transporter(LAT1), bridged with a phenylboronic acid-containing linker. By harnessing the LAT1-mediated direct transport mechanism, the optimized pro-protein, named protein-M2-D, can efficiently penetrate BBB after i.v. injection, and subsequently enable selective and endocytosis-free delivery of various proteins including enzymes, toxins, and antibodies into glioblastoma cells, wherein intracellular H_(2)O_(2) triggered traceless restoration of the native protein structure. Systemic administration of saporin-M2-D provoked potent anti-tumor efficacy against orthotopic U87 glioblastoma in mice, without inducing systemic toxicity. Such a facile, versatile, and robust platform renders a promising paradigm for cytosolic protein delivery and glioblastoma treatment.展开更多
基金the financial support from the National Natural Science Foundation of China(No.51873213)Science and Technology Program of Suzhou(No.SKY2022111)Collaborative Innovation Center of Suzhou Nano Science&Technology,and FUNSOM Self-Directed Research Project(No.2022)。
文摘Planktonic bacteria adhere and subsequently form biofilms on implantable medical devices can cause severe infections that have become the major types of hospital-acquired infections.Traditional coatings for the implants are frequently lack of long-term antifouling and bactericidal activities.It is still a big challenge to simultaneously improve the antifouling and bactericidal activities of the coatings.Herein,we report that mixed-charge glycopolypeptide coatings are of long-term antibacterial activities to efficiently inhibit the biofilm growth.The glycosylation of mixed-charge polypeptides has led to a significant improvement of both antifouling and bactericidal activities.The cooperative effect of the saccharide residues and mixed-charge residues improved the resistance of the polypeptide coatings against protein adsorption.The saccharide and L-glutamic acid(E)residues collectively enhanced the bacterial membrane-disruption of cationic L-lysine(K)residues,leading to potent bactericidal activity.Meanwhile,the glycopolypeptide coatings showed superior biocompatibility,long-term antibiofilm and anti-infection properties in two types of mouse subcutaneous infection models and one type of mouse urinary tract infection model.This work provides a new strategy to achieve antibacterial coatings with long-term activities for preventing implantable medical device associated infections.
基金National Natural Science Foundation of China,Grant/Award Numbers:52273144,52325305,82241008Collaborative Innovation Center of Suzhou Nano Science&Technology+1 种基金Suzhou Key Laboratory of Nanotechnology and BiomedicineJoint International Research Laboratory of Carbon-Based Functional Materials and Devices。
文摘Immunotherapy has recently emerged as a promising therapeutic modality for the treatment of various diseases such as cancer,inflammation,autoimmune diseases,and infectious diseases.Despite its potential,immunotherapy faces challenges related to delivery efficiency and off-target toxicity of immunotherapeutic drugs.Nano drug delivery systems offer improvements in drug biodistribution and release kinetics but still suffer from shortcomings such as high immunogenicity,poor penetration across biological barriers,and insufficient tissue permeability.Targeted delivery of drugs using living cells has become an emerging strategy that can take advantage of the inherent characteristics of cells to deal with the delivery defects of nano delivery systems.Furthermore,cells themselves can be genetically engineered into cellular drugs for enhanced immunotherapy.This review provides an in-depth exploration of cell-derived drug carriers,detailing their biological properties,functions,and commonly used drug loading strategies.In addition,the role of genetically modified cells in immunotherapy and their synergistic therapeutic effects with drug delivery are also introduced.By summarizing the main advancements and limitations in the field,this review offers insights into the potential of cell-based drug delivery systems to address the existing challenges in immunotherapy.The introduction to recent developments and evaluation of ongoing research will pave the way for the optimization and widespread adoption of nano/genetically engineered cells for immunotherapy.
基金supported by the Natural Science Foundation of Jiangsu Province(No.BK20220245)the National Natural Science Foundation of China(Nos.52273144 and 82241008)Collaborative Innovation Center of Suzhou Nano Science&Technology,the 111 project,Suzhou Key Laboratory of Nanotechnology and Biomedicine,and Joint International Research Laboratory of Carbon-Based Functional Materials and Devices.
文摘Intracellular protein delivery is critical to the development of protein-based biopharmaceuticals and therapies.However,current delivery vectors often suffer from complicated syntheses,low generality among various proteins,and insufficient serum stability.Herein,we developed an enlightened cytosolic protein delivery strategy by dynamically crosslinking epigallocatechin gallate(EGCG),low-molecular-weight polyethylenimine(PEI 1.8k),and 2-acetylphenylboric acid(2-APBA)on the protein surface,hence forming the EPP-protein nanocapsules(NCs).EGCG enhanced protein encapsulation via hydrogen bonding,and reduced the positive charge density of PEI to endow the NCs with high serum tolerance,thereby enabling effective cellular internalization in serum.The formation of reversible imine and boronate ester among 2-APBA,EGCG,and PEI 1.8k allowed acid-triggered dissociation of EPP-protein NCs in the endolysosomes,which triggered efficient intracellular release of the native proteins.Such strategy therefore showed high efficiency and universality for diversities of proteins with different molecular weights and isoelectric points,including enzyme,toxin,antibody,and CRISPR(clustered regularly interspaced short palindromic repeats)-Cas9 ribonucleoprotein(RNP),outperforming the commercial protein transduction reagent PULSin and RNP transfection reagent lipofectamine CMAX.Moreover,intravenously(i.v.)injected EPP-saporin NCs efficiently delivered saporin into 4T1 tumor cells to provoke robust antitumor effect.This simple,versatile,and robust cytosolic protein delivery system holds translational potentials for the development of protein-based therapeutics.
文摘Polymeric micelles have demonstrated wide utility for chemodrug delivery,which however,still suffer from shortcomings such as undesired drug loading,disassembly upon dilution,pre-leakage of drug cargoes during systemic circulation,and lack of cancer-selective drug release.Herein,a poly(ethylene glycol)(PEG)-polyphosphoester-based,reactive oxygen species (ROS)-responsive,core-cross-linked (CCL) micellar system was developed to encapsulate both chemodrug (doxorubicin,Dox) and photosensitizer (chlorin e6,Ce6).The hydrophobic core of the micelles was cross-linked via a thioketal (TK)-containing linker,which notably enhanced the drug loading and micelle stability.In tumor cells,far-red light irradiation of Ce6 generated ROS to cleave the TK linkers and disrupt the micelle cores.As such,micelles were destabilized and Dox release was promoted,which thereafter imparted synergistic anti-cancer effect with ROS-mediated photodynamic therapy.This study provides an effective approach to realize the precise control over drug loading,formulation stability,and cancer-selective drug release using polymeric micelles,and would render promising utilities for the programmed anti-cancer combination therapy.
基金supported by the National Natural Science Foundation of China (52073218, 22135005, 51873162, 51933006,51988102, 52122310, 22075050, 51833008, 51733006, 51733001,52122304)Jiangsu Province Science Foundation for Youths(BK20200241)+3 种基金Science and Technology Commission of Shanghai Municipality (20JC1414902, 21511104900)Shanghai Municipal Education Commission (2017-01-07-00-07-E00062)the National Key Research and Development Program (2021YFA1201200) of Chinathe Zhejiang Provincial Key Research and Development Program (2020C01123)。
文摘Biomedical polymers have been extensively developed for promising applications in a lot of biomedical fields, such as therapeutic medicine delivery, disease detection and diagnosis, biosensing, regenerative medicine, and disease treatment. In this review, we summarize the most recent advances in the synthesis and application of biomedical polymers, and discuss the comprehensive understanding of their property-function relationship for corresponding biomedical applications. In particular, a few burgeoning bioactive polymers, such as peptide/biomembrane/microorganism/cell-based biomedical polymers, are also introduced and highlighted as the emerging biomaterials for cancer precision therapy. Furthermore, the foreseeable challenges and outlook of the development of more efficient, healthier and safer biomedical polymers are discussed. We wish this systemic and comprehensive review on highlighting frontier progress of biomedical polymers could inspire and promote new breakthrough in fundamental research and clinical translation.
基金National Natural Science Foundation of China (Nos. 51573123, 51722305, and 51633005)the Ministry of Science and Technology of China (No. 2016YFA0201200) 111 projectPriority Academic Program Development of Jiangsu Higher Education Institutions (PAPD).
文摘Co-delivery of anti-inflammatory siRNA and hydrophilic drug provides a promising approach for the treatment of ulcerative colitis (UC). However, lack of a suitable and efficient co-delivery carrier poses critical challenge against their utilization. We herein developed macrophage-targeting, reversibly crossli nked polymersomes (TKPR-RCP) based on the TKPR-modified, poly(ethyle ne glycol)-b-poly(trimethylene carbonate-codithiolane trimethylene carbonate)-b-polyethylenimine (PEG-P(TMC-DTC)-PEI) triblock copolymer, which could efficiently encapsulate TNF-α siRNA and dexamethasone sodium phosphate (DSP) in their hydrophilic core. The cationic PEI segments provided additional electrostatic interactions with cargo molecules to promote the encapsulatiion, and disulfide crosslinking of the polymersome membrane endowed the TKPR-RCP with high colloidal stability. Because the cationic PEI was embedded in the hydrophilic core, the polymersomes displayed neutral surface charge and thus possessed high serum stability. The TKPR-RCP co-encapsulating TNF-α siRNA and DSP could be efficiently internalized by macrophages (~98%) and undergo redox-responsive membrane de-crosslinking to accelerate cargo release in the cytoplasm, thus inducing efficient gene silencing and anti-inflammatory effect .Intravenous injectio n of the co-delivery TKPR-RCP mediated pote nt and cooperative anti-inflammatory effect in inflamed colons of UC mice, and significantly prevented animals from colonic injury. This study therefore provides a promising approach for the co-delivery of hydrophilic drug/siRNA toward the treatment of inflammatory bowel diseases.
基金The research was financially supported by the National Natural Science Foundation of China(Nos.51873142,51722305,and 81903068)the Ministry of Science and Technology of China(No.2016YFA0201200)111 project,and the Priority Academic Program Development of Jiangsu Higher Education Institutions(PAPD).
文摘Insufficient intratumoral penetration greatly hurdles the anticancer performance of nanomedicine. To realize highly efficient tumor penetration in a precisely and spatiotemporally controlled manner, far-red light-responsive nanoclusters (NCs) capable of size shrinkage and charge conversion were developed and co-administered with iRGD to synergistically improve the intratumoral penetration and the anticancer efficacy. The NCs were constructed using the singlet oxygen-sensitive (SOS) polyethylene glycolpolyurethane-polyethylene glycol (PEG-(1O2)PU-PEG) triblock copolymer to encapsulate the doxorubicin (DOX)-loaded, chlorin e6 (Ce6)-conjugated polyamindoamine (PAMAM) dendrimer (DCD) via the double-emulsion method. Co-administration of iRGD notably increased the permeability of NCs within tumor vasculature and tumor tissues. In addition, upon far-red light irradiation (660 nm) of tumors at low optical density (10 mW/cm2), the generated 1O2 could disintegrate the NCs and release the DCD with positive surface charge and ultra-small size (~ 5 nm), which synergized with iRGD to enable deep intratumoral penetration. Consequently, the local 1O2 at lethal concentrations along with the released DOX efficiently and cooperatively eradicated tumor cells. This study provides a convenient approach to spatiotemporally promote the intratumoral penetration of nanomedicine and mediate programmed anticancer therapy.
基金This work was supported by the National Natural Science Foundation of China(82172076,51873142,and 52033006)Jiangsu Key Research and Development Plan(Social Development)Project(BE2020653 and BE2021642)+1 种基金Suzhou Science and Technology Development Project(SYS2019072)Collaborative Innovation Center of Suzhou Nano Science&Technology,the 111 project,Suzhou Key Laboratory of Nanotech-nology and Biomedicine,and Joint International Research Laboratory of Carbon-Based Functional Materials and Devices.
文摘Ischemia-reperfusion (IR) injury represents a major cause of myocardial dysfunction after infarction and thrombolytic therapy, and it is closely related to the free radical explosion and overwhelming inflammatory responses. Herein, macrophage-targeting nanocomplexes (NCs) are developed to mediate efficient co-delivery of siRNA against MOF (siMOF) and microRNA-21 (miR21) into myocardial macrophages, cooperatively orches-trating the myocardial microenvironment against IR injury. Bioreducible, branched poly(β-amino ester) (BPAE-SS) is designed to co-condense siMOF and miR21 into NCs in a multivalency-reinforced approach, and they are surface-decorated with carboxylated mannan (Man-COOH) to shield the positive surface charges and enhance the serum stability. The final MBSsm NCs are efficiently internalized by myocardial macrophages after systemic administration, wherein BPAE-SS is degraded into small segments by intracellular glutathione to promote the siMOF/miR21 release, finally provoking efficient gene silencing. Thus, cardiomyocyte protection and macro-phage modulation are realized via the combined effects of ROS scavenging, inflammation inhibition, and autophagy attenuation, which ameliorates the myocardial microenvironment and restores the cardiac function via positive cellular crosstalk. This study renders promising solutions to address the multiple systemic barriers against in vivo nucleic acid delivery, and it also offers new options for IR injury by manipulating multiple reciprocal bio-reactions.
基金funding support from the National Natural Science Foundation of China(No.52033006 and 51873142)Suzhou Science and Technology Development Project(No.SYS2019072) Science Foundation of China (No. 52033006 and 51873142)+1 种基金Suzhou Science and Technology Development Project (No.SYS2019072), Collaborative Innovation Center of Suzhou NanoScience & Technology, the 111 project, Suzhou Key Laboratory ofNanotechnology and BiomedicineJoint InternationalResearch Laboratory of Carbon-Based Functional Materials andDevices。
文摘Myocardial ischemia reperfusion(IR)injury is closely related to the overwhelming inflammation in the myocardium.Herein,cardiomyocyte-targeted nanotherapeutics were developed for the reactive oxygen species(ROS)-ultrasensitive co-delivery of dexamethasone(Dex)and RAGE small interfering RNA(siRAGE)to attenuate myocardial inflammation.PPTP,a ROSdegradable polycation based on PGE2-modified,PEGylated,ditellurium-crosslinked polyethylenimine(PEI)was developed to surface-decorate the Dex-encapsulated mesoporous silica nanoparticles(MSNs),which simultaneously condensed siRAGE and gated the MSNs to prevent the Dex pre-leakage.Upon intravenous injection to IR-injured rats,the nanotherapeutics could be efficiently transported into the inflamed cardiomyocytes via PGE2-assisted recognition of over-expressed E-series of prostaglandin(EP)receptors on the cell membranes.Intracellularly,the over-produced ROS degraded PPTP into small segments,promoting the release of siRAGE and Dex to mediate effective RAGE silencing(72%)and cooperative antiinflammatory effect.As a consequence,the nanotherapeutics notably suppressed the myocardial fibrosis and apoptosis,ultimately recovering the systolic function.Therefore,the current nanotherapeutics represent an effective example for the codelivery and on-demand release of nucleic acid and chemodrug payloads,and might find promising utilities toward the synergistic management of myocardial inflammation.
基金supported by the National Natural Science Foundation of China(22101194 and 52273144)Science and Technology Department of Jiangsu Province(BK20210733).
文摘While the accelerated polymerization of N-carboxyanhydrides (NCAs) has been utilized to synthesize versatile polypeptide materials in an efficient manner with minimized side reactions, the preparation of polypeptide-based inorganic/organic hybrid materials with the acceleration strategy remained largely unexplored. Herein, we report the accelerated ring-opening polymerization (ROP) of NCAs mediated by amine-modified inorganic nano-initiators, such as mesoporous silica nanoparticles (MSN-NH2), which is driven by the cooperative effect of the neighboring α-helical polypeptide chains in a dichloromethane (DCM)/water biphasic system. Well-defined nano-hybrids were prepared within 15 min from non-purified NCA monomers, through in situ purification and subsequent ultrafast polymerization process. NCAs can be rapidly initiated by amino groups of MSN uniformly dispersed at the interface of DCM and water, and subsequently formed the well-defined polypeptides within 15 min. The prepared inorganic/organic nano-hybrid with MSN as the core and polypeptide as the shell adopted spherical morphology and uniform size distribution due to the excellent controllability of ROP. Besides, this system is also suitable for a variety of NCAs and inorganic nano-initiators. This research allows efficient and rapid preparation of inorganic/organic nano-hybrids, and further promotes the extensive application of this material in the biomedical fields.
基金supported by the National Natural Science Foundation of China(Nos.82172076,52273144,and 52033006)111 project,Collaborative Innovation Center of Suzhou Nano Science&Technology,Joint International Research Laboratory of Carbon-Based Functional Materials and Devices,and Suzhou Key Laboratory of Nanotechnology and Biomedicine.
文摘MicroRNA-208a(miR-208a)plays critical roles in the severe fibrosis and heart failure post myocardial ischemia/reperfusion(IR)injury.MiR-208a inhibitor(mI)with complementary RNA sequence can silence the expression of miR-208a,while it is challenging to achieve efficient and myocardium-targeted delivery.Herein,biomimetic nanocomplexes(NCs)reversibly coated with red blood cell membrane(RM)were developed for the myocardial delivery of mI.To construct the NCs,membrane-penetrating helical polypeptide(PG)was first adopted to condense mI and form the cationic inner core,which subsequently adsorbed catalase(CAT)via electrostatic interaction followed by surface coating with RM.The membrane-coated NCs enabled prolonged blood circulation after systemic administration,and could accumulate in the injured myocardium via passive targeting.In the oxidative microenvironment of injured myocardium,CAT decomposed H_(2)O_(2)to produce O_(2)bubbles,which drove the shedding of the outer RM to expose the positively charged inner core,thus facilitated effective internalization by cardiac cells.Based on the combined contribution of mI-mediated miR-208a silencing and CAT-mediated alleviation of oxidative stress,NCs effectively ameliorated the myocardial microenvironment,hence reducing the infarct size as well as fibrosis and promoting recovery of cardiac functions.This study provides an effective strategy for the cytosolic delivery of nucleic acid cargoes in the myocardium,and it renders an enlightened approach to resolve the blood circulation/cell internalization dilemma of cell membrane-coated delivery systems.
基金supported by the Natural Science Foundation of Jiangsu Province (BK20220245)the National Natural Science Foundation of China (52325305, 82241008, 52033006)+4 种基金Jiangsu Key Research and Development Plan (Social Development) Project (BE2020653, BE2021642)the Collaborative Innovation Center of Suzhou Nano Science & Technologythe 111 projectSuzhou Key Laboratory of Nanotechnology and BiomedicineJoint International Research Laboratory of Carbon-Based Functional Materials and Devices。
文摘Intracellular protein therapeutics holds great potentials for the treatment of glioblastoma, which however, is greatly challenged by the unmet demands to concomitantly penetrate the blood-brain barrier(BBB) and glioblastoma cell membrane barrier with high efficiency and selectivity. Herein, a unique pro-protein platform was developed via facile green synthesis, which allowed efficient and selective delivery into glioblastoma cells in a carrier-free manner. Pro-proteins were engineered via reversible modification of native proteins in the aqueous buffer with 3,4-dihydroxy-phenylalanine, the substrate of L-type amino acid transporter(LAT1), bridged with a phenylboronic acid-containing linker. By harnessing the LAT1-mediated direct transport mechanism, the optimized pro-protein, named protein-M2-D, can efficiently penetrate BBB after i.v. injection, and subsequently enable selective and endocytosis-free delivery of various proteins including enzymes, toxins, and antibodies into glioblastoma cells, wherein intracellular H_(2)O_(2) triggered traceless restoration of the native protein structure. Systemic administration of saporin-M2-D provoked potent anti-tumor efficacy against orthotopic U87 glioblastoma in mice, without inducing systemic toxicity. Such a facile, versatile, and robust platform renders a promising paradigm for cytosolic protein delivery and glioblastoma treatment.
