The development of large-scale cell cultivation and non-invasive cell harvesting is highly desired in various fields,including biological regeneration and pharmaceutical research.When using traditional microcarriers f...The development of large-scale cell cultivation and non-invasive cell harvesting is highly desired in various fields,including biological regeneration and pharmaceutical research.When using traditional microcarriers for cell culture,trypsinization is often necessary during cell collection,leading to partial cells damage.In this work,we developed a thermoresponsive glass microcarrier modified with poly(γ-propargyl-L-glutamate)(PPLG)and poly(N-isopropylacrylamide)(PNIPAM).We utilized these microcarriers for three-dimensional cell culture and enzyme-free cell harvesting,and the results indicated that the prepared microcarriers exhibited excellent non-invasive cell culture performance.展开更多
Tumor vaccines trigger tumor-specific immune responses to prevent or treat tumors by activating the hosts’immune systems,and therefore,these vaccines have potential clinical applications.However,the low immunogenicit...Tumor vaccines trigger tumor-specific immune responses to prevent or treat tumors by activating the hosts’immune systems,and therefore,these vaccines have potential clinical applications.However,the low immunogenicity of the tumor antigen itself and the low efficiency of the vaccine delivery system hinder the efficacy of tumor vaccines that cannot produce high-efficiency and long-lasting antitumor immune effects.Here,we constructed a nanovaccine by integrating CD47KO/CRT dual-bioengineered B16F10 cancer cell membranes and the unmethylated cytosine-phosphate-guanine(CpG)adjuvant.Hyperbranched PEI25k was used to load unmethylated cytosine-phosphate-guanine(CpG)through electrostatic adsorption to prepare PEI25k/CpG nanoparticles(PEI25k/CpG-NPs).CD47KO/CRT dual-bioengineered cells were obtained by CRISPR-Cas9 gene editing technology,followed by the cell surface translocation of calreticulin(CRT)to induce immunogenic cell death(ICD)in vitro.Finally,the extracted cell membranes were coextruded with PEI25k/CpG-NPs to construct the CD47KO/CRT dual-bioengineered cancer cell membrane-coated nanoparticles(DBE@CCNPs).DBE@CCNPs could promote endocytosis of antigens and adjuvants in murine bone marrow derived dendritic cells(BMDCs)and induce their maturation and antigen cross-presentation.To avoid immune checkpoint molecule-induced T cell dysfunction,the immune checkpoint inhibitor,the anti-PD-L1 antibody,was introduced to boost tumor immunotherapy through a combination with the DBE@CCNPs nanovaccine.This combination therapy strategy can significantly alleviate tumor growth and may open up a potential strategy for clinical tumor immunotherapy.展开更多
As a revolutionary cancer treatment strategy,immunotherapy has attracted great attention.However,the effect of immunotherapy such as immune checkpoint blockade(ICB)is usually limited by insufficient immune response in...As a revolutionary cancer treatment strategy,immunotherapy has attracted great attention.However,the effect of immunotherapy such as immune checkpoint blockade(ICB)is usually limited by insufficient immune response in the body.Herein,a polycation-based magnetic nanocluster platform was developed to load therapeutic nucleic acids,which could achieve gene therapy-mediated ICB and efficient magnetic hyperthermia therapy(MHT).The silencing of immune checkpoints together with MHT-induced immunogenic cell death(ICD)effectively alleviated the immune escape of cancer cells and significantly enhanced the visibility of cancer cells to the immune system.This combined treatment strategy activated a strong adaptive anti-cancer immune response in vivo,greatly inhibiting tumor growth,metastasis and recurrence.展开更多
The low objective response rates and severe side effects largely limit the clinical outcomes of immune checkpoint blockade(ICB)therapy.Here,a tumor“self-killing”therapy based on gene-guided OX40L anchoring to tumor ...The low objective response rates and severe side effects largely limit the clinical outcomes of immune checkpoint blockade(ICB)therapy.Here,a tumor“self-killing”therapy based on gene-guided OX40L anchoring to tumor cell membrane was reported to boost ICB therapy.We developed a highly efficient delivery system HA/PEI-KT(HKT)to co-deliver the OX40L plasmids and unmethylated CG-enriched oligodeoxynucleotide(CpG).On the one hand,CpG induced the expression of OX40 on T cells within tumors.On the other hand,OX40L plasmids achieved the OX40L anchoring on the tumor cell membrane to next promote T cells responses via OX40/OX40L axis.Such synergistic tumor“self-killing”strategy finally turned“cold”tumors to“hot”,to sensitize tumors to programmed cell death protein 1/programmed cell death ligand 1(PD-1/PD-L1)blockade therapy,and promoted an immune-mediated tumor regression in both B16F10 and 4T1 tumor models,with prevention of tumor recurrence and metastasis.To avoid the side effects,the gene-guided OX40L anchoring and PD-L1 silencing was proposed to replace the existing antibody therapy,which showed negligible toxicity in vivo.Our work provided a new possibility for tumor“self-killing”immunotherapy to treated various solid tumors.展开更多
Precise nanomedicine has been extensively explored for efficient cancer imaging and targeted cancer therapy, as evidenced by a few breakthroughs in their preclinical and clinical explorations. Here, we demonstrate the...Precise nanomedicine has been extensively explored for efficient cancer imaging and targeted cancer therapy, as evidenced by a few breakthroughs in their preclinical and clinical explorations. Here, we demonstrate the recent advances of intelligent cancer nanomedicine, and discuss the comprehensive understanding of their structure-function relationship for smart and efficient cancer nanomedicine including various imaging and therapeutic applications, as well as nanotoxicity. In particular, a few emerging strategies that have advanced cancer nanomedicine are also highlighted as the emerging focus such as tumor imprisonment, supramolecular chemotherapy, and DNA nanorobot. The challenge and outlook of some scientific and engineering issues are also discussed in future development. We wish to highlight these new progress of precise nanomedicine with the ultimate goal to inspire more successful explorations of intelligent nanoparticles for future clinical translations.展开更多
Despite of the promising achievements of immune checkpoints blockade therapy(ICB) in the clinic,which was often limited by low objective responses and severe side effects.Herein,we explored a synergistic strategy to c...Despite of the promising achievements of immune checkpoints blockade therapy(ICB) in the clinic,which was often limited by low objective responses and severe side effects.Herein,we explored a synergistic strategy to combine in situ vaccination and gene-mediated anti-PD therapy,which was generated by unmethylated cytosine-phosphate-guanine(CpG) and pshPD-L1 gene co-delivery.PEI worked as the delivery carrier to co-deliver the CpG and pshPD-L1 genes,the formed PDC(PEI/DNA/CpG)nanoparticles were further shielded by aldehyde modified polyethylene glycol(OHC-PEG-CHO) via pH responsive Schiff base reaction for OHC-PEG-CHO-PEI/DNA/CpG nanoparticles(P(PDC) NPs) prepa ration.All steps could be finished within 30 min.Such simple nanoparticles achieved the synergistic antitumor efficacy in B16 F10 tumor-bearing mice,and the amplified T cell responses,together with enhanced NK cells infiltration were observed after the combined treatments.In addition,the pH responsive delivery system reduced the side effects triggered by anti-PD therapy.The facile and effective combination strategy we presented here might provide a novel treatment for tumor inhibition.展开更多
A novel amphiphilic cationic block copolymer polylysine-b-polyphenylalanine(PLL-b-PPhe)was synthesized and self-assembled into micelles in aqueous solution,then shielded with poly(glutamic acid)(marked as PG/PLL-b-PPh...A novel amphiphilic cationic block copolymer polylysine-b-polyphenylalanine(PLL-b-PPhe)was synthesized and self-assembled into micelles in aqueous solution,then shielded with poly(glutamic acid)(marked as PG/PLL-b-PPhe)to codeliver gene and drug for combination cancer therapy.Here,doxorubicin(DOX)was selected to be loaded into PLL-b-PPhe micelles and the drug loading efficiency was 8.0%.The drug release studies revealed that the PLL-b-PPhe micelles were pH sensitive and the released DOX could reach to 53.0%,65.0%,72.0%at pH 7.4,6.8 and 5.0,respectively.In order to reduce positive charge and cytotoxicity of PLL-b-PPhe micelles,PG was used as shelding,simultaneously condensed with Bcl2 siRNA to form gene carrier system.Compared with PEI,PG/PLL-b-PPhe had excellent gene transfection efficiency,especially when the molar ratio of PLL to PPhe was 30:60 and the mixed mass ratio of PLL-b-PPhe to gene was 5:1.More importantly,DOX and Bcl2 siRNA gene codelivery system displayed remarkable cytotoxicity against B16 F10 cells.Confocal laser scanning microscopy(CLSM)and flow cytometry were used to characterize endocytosis of the codelivery system,and confirmed that both DOX and Bcl2 siRNA had been endocytosed into B16 F10 cells.The above results indicated that gene and drug codelivery was a promising strategy in future cancer therapy.展开更多
Nano-therapeutic approach for clinical implementation of tumors remains a longstanding challenge in the medical field. The main challenges are rapid clearance, offtarget effect and the limited role in the treatment of...Nano-therapeutic approach for clinical implementation of tumors remains a longstanding challenge in the medical field. The main challenges are rapid clearance, offtarget effect and the limited role in the treatment of metastatic tumors. Toward this objective, a cell-mediated strategy by transporting photothermal reagents and CpG adjuvant within macrophage vehicles is performed. The photothermal reagents are constructed by conjugating of hyperbranched polyethyleimine（PEI） to golden nanorode（GNR） via S-Au bonds.GNR-PEI/CpG nanocomposites, formed via electrostatic interaction and displayed excellent near-infrared（NIR） photothermal performance, exhibit immense macrophage uptake and negligible cytotoxic effect, which is essential for the fabrication of GNR-PEI/CpG loaded macrophages. GNR-PEI/CpG loaded macrophages demonstrated admirable photothermal response in vitro. Benefited from the functionalization of the binding adhesion between macrophages and 4 T1 cells, GNR-PEI/CpG loaded macrophages significantly promoted tumor accumulation in vivo and dramatically enhanced the efficiency of photothermal cancer therapy. Moreover, the immune system is activated after photothermal therapy, which is mainly attributed to the generation of tumor specific antigens and CpG adjuvant in situ. Our findings provide a potential cell-mediated nanoplatform for tumor therapy by combination of near infrared photothermal therapy and immunotherapy.展开更多
Gold nanoparticles have seen unprecedented development in the biomedical field, particularly for cancer ther- apy. They have received extensive attention because of their easy preparation, functionalization, biocompat...Gold nanoparticles have seen unprecedented development in the biomedical field, particularly for cancer ther- apy. They have received extensive attention because of their easy preparation, functionalization, biocompatibility, non-cytotoxicity, and detectability. Functionalized gold nanoparticles can be applied in the fields of drug and gene delivery, photothermal therapy, and bioimaging. This review introduces methods for preparing various shapes of gold nanoparticles and describes their current applications in the field of cancer treatment. Moreover, the review presents the development routes and current issues of gold nanoparticles in clinical theranostics.展开更多
Tumor nanovaccines have potential applications in the prevention and treatment of malignant tumors.However,it remains a longstanding challenge in exploiting efficient nanocarriers for inducing potent specifically cell...Tumor nanovaccines have potential applications in the prevention and treatment of malignant tumors.However,it remains a longstanding challenge in exploiting efficient nanocarriers for inducing potent specifically cellular immune responses.Toward this objective,we herein explore an intensive tumor immunotherapeutic strategy by combining mannosylated nanovaccines and gene regulated PD-L1 blockade for immune stimulation and killing activity.Here,we fabricate a mannose modified PLL-RT(Man-PLL-RT)mediated nanovaccines with dendritic cells(DCs)targeting capacity.Man-PLL-RT is capable of co-encapsulating with antigen(ovalbumin,OVA)and adjuvant(unmethylated cytosine-phosphate-guanine,CpG)by electrostatic interaction.This positively charged Man-PLL-RT/OVA/CpG nanovaccines can facilitate the endocytosis,maturation and cross presentation in DCs.However,the nanovaccines arouse limited inhibition of tumor growth,which is mainly due to the immunosuppressed microenvironment of tumors.Combining tumor nanovaccines with gene regulated PD-L1 blockade leads to an obvious tumor remission in B16F10 melanoma bearing mice.The collaborative strategy provides essential insights to boost the benefits of tumor vaccines by regulating the checkpoint blockade with gene therapy.展开更多
In recent years,various carriers for gene delivery nave been developed for biomedical applications.Among all kinds of gene carriers,cationic polymeric carriers for delivery therapeutic gene as non-viral carriers have ...In recent years,various carriers for gene delivery nave been developed for biomedical applications.Among all kinds of gene carriers,cationic polymeric carriers for delivery therapeutic gene as non-viral carriers have received growing interests due to their improved high transfection efficiency with the relative safety.In particular,the advancement of novel polymeric gene carriers has gained much progress in the development of effective anticancer therapy.Herein,this review focused on the development of cationic polymeric carriers for cancer therapy,including polyethylenimine(PEI),polyamidoamine(PAMAM) dendrimers,polylysine(PLL),chitosan and modified cationic polymers.And recent progresses in the development of novel polymeric carriers for gene delivery,such as targeted gene carriers,responsive gene carriers and multifunctional gene carriers,were summarized.Finally,the future perspectives in the development of novel polymeric carriers for delivery gene were presented.展开更多
Obesity has become an important public problem that endangers human conditions and urgently needs to be solved. However,most weight-loss drugs on the market have little effect and are accompanied by adverse effects su...Obesity has become an important public problem that endangers human conditions and urgently needs to be solved. However,most weight-loss drugs on the market have little effect and are accompanied by adverse effects such as strokes and heart attacks.Here, we construct an adipocyte-targeting polypeptide-based gene carrier consisting of an adipocyte-targeting peptide and ptoluylsulfonyl arginine-modified polylysine(ATS-PLL-RT), which can specifically bind to the prohibitin of mature adipocytes.We further construct a short hairpin RNA(shRNA) to simultaneously silence fatty acid binding proteins 4 and 5(shFABP4/5).FABPs are molecular chaperones for fatty acid metabolism and storage in cells. Moreover, we introduce metformin for combined therapy. First, the metformin combination can effectively improve the efficiency of gene transfection. In addition, metformin itself has an alleviating effect on diet-induced obesity and relevant metabolic diseases. The combination treatment of obese mice with ATS-PLL-RT/shFABP4/5 and metformin achieves body weight reduction and metabolic recovery. This study provides a potentially effective strategy for the clinical treatment of obesity as well as mitigating obesity-induced metabolic syndromes.展开更多
Covalent organic framework(COF)materials have great development value in the biomedical field.However,the huge size and poor dispersion of COF materials severely limit their application.Here we successfully prepared C...Covalent organic framework(COF)materials have great development value in the biomedical field.However,the huge size and poor dispersion of COF materials severely limit their application.Here we successfully prepared COF nanoparticles with uniform size and good dispersion under the assistance of microwave.By adding some cationic polymers or small amine molecules,the dispersibility of COF could be further improved and its surface charge also increased.The prepared cationic COF nanoparticles(CLZU NPs)had excellent gene transfection ability and good biocompatibility.Designing low-toxic and highefficiency gene carrier is an important mission in the field of gene therapy.This COF-based gene vector provides a new direction for gene carrier design.展开更多
Currently,reactive oxygen species(ROS)generation primarily depends upon light and O2,which hampers its further biomedical application.Here,we report that amanganese(Ⅲ)salen-based complex(MnS)can continuously catalyze...Currently,reactive oxygen species(ROS)generation primarily depends upon light and O2,which hampers its further biomedical application.Here,we report that amanganese(Ⅲ)salen-based complex(MnS)can continuously catalyze overexpressed hydrogen peroxide(H_(2)O_(2))in the tumor microenvironment to ^(1)O_(2),while the nanocarrier(MIL-100)as a Fenton reagent can convert H_(2)O_(2) to hydroxyl radicals(·OH)through the Fenton reaction,inducing noticeable intracellular DNA strand scission and lipid peroxidation to provoke tumor cell apoptosis without the involvement of light and O_(2).Moreover,MIL-100 depleted the antioxidant glutathione,further amplifying intracellular oxidative pressure,which in turn led to the self-degradation of MIL-100,suggesting the long-term biosafety of the nanoplatform.Owing to the excellent magnetic resonance imaging performance of MnS,the diagnosis and specific treatment of tumors were eventually achieved.This work provides a novel approach for the realization of effective tumor catalytic therapy independent of light and O_(2) and a promising reference for the development of a wide range of catalytic therapeutic agents.展开更多
The complex and rapidly progressing nature of sepsis calls for the development of multifunctional and rapid-acting therapeutic agents,instead of single-modal treatments.To address this challenge,a biodegradable,easily...The complex and rapidly progressing nature of sepsis calls for the development of multifunctional and rapid-acting therapeutic agents,instead of single-modal treatments.To address this challenge,a biodegradable,easily synthesized,and antibiotic-free multifunctional nanoparticle has been created for sepsis therapy.The nanoparticle was formed by the electrostatic interaction between two endogenous small molecule-derived polymers,poly(lipoic acid)and poly-lysine,and possessed various functions such as antibacterial activity,adsorption of cell-free DNA,scavenging of reactive oxygen and nitrogen species,providing a comprehensive approach to combating sepsis.Treatment using the cecal ligation and puncture(CLP)model confirmed the therapeutic benefits of the nanoparticles,demonstrating reduced levels of reactive oxygen across multiple organs,diminished levels of M1 proinflammatory macrophages,and elevated levels of M2 anti-inflammatory macrophages post-treatment.These findings emphasized the effectiveness of the nanoparticles in sepsis therapy,and properties of degradation,easy preparation,and swift therapeutic response made them promising for the future clinical applications.展开更多
基金supported by the name of National Key Research and Development Program of China(No.2021YFB3800900)the National Natural Science Foundation of China(Nos.51925305,51873208,1833010,51973217,52373161)Jilin Province Science and Technology Development Program(No.20200201075JC)。
文摘The development of large-scale cell cultivation and non-invasive cell harvesting is highly desired in various fields,including biological regeneration and pharmaceutical research.When using traditional microcarriers for cell culture,trypsinization is often necessary during cell collection,leading to partial cells damage.In this work,we developed a thermoresponsive glass microcarrier modified with poly(γ-propargyl-L-glutamate)(PPLG)and poly(N-isopropylacrylamide)(PNIPAM).We utilized these microcarriers for three-dimensional cell culture and enzyme-free cell harvesting,and the results indicated that the prepared microcarriers exhibited excellent non-invasive cell culture performance.
基金The authors are thankful to the National Key R&D Program of China(2021YFB3800900)National Natural Science Foundation of China(51925305,51873208,51973217)+2 种基金Taishan Scholar Foundation of Shandong Province(qnts20161035)Natural Science Foundation of Shandong Province(ZR2019ZD24,ZR2019YQ30)Jilin Province Science and Technology Development Program(20200201075JC,20210509005RQ).
文摘Tumor vaccines trigger tumor-specific immune responses to prevent or treat tumors by activating the hosts’immune systems,and therefore,these vaccines have potential clinical applications.However,the low immunogenicity of the tumor antigen itself and the low efficiency of the vaccine delivery system hinder the efficacy of tumor vaccines that cannot produce high-efficiency and long-lasting antitumor immune effects.Here,we constructed a nanovaccine by integrating CD47KO/CRT dual-bioengineered B16F10 cancer cell membranes and the unmethylated cytosine-phosphate-guanine(CpG)adjuvant.Hyperbranched PEI25k was used to load unmethylated cytosine-phosphate-guanine(CpG)through electrostatic adsorption to prepare PEI25k/CpG nanoparticles(PEI25k/CpG-NPs).CD47KO/CRT dual-bioengineered cells were obtained by CRISPR-Cas9 gene editing technology,followed by the cell surface translocation of calreticulin(CRT)to induce immunogenic cell death(ICD)in vitro.Finally,the extracted cell membranes were coextruded with PEI25k/CpG-NPs to construct the CD47KO/CRT dual-bioengineered cancer cell membrane-coated nanoparticles(DBE@CCNPs).DBE@CCNPs could promote endocytosis of antigens and adjuvants in murine bone marrow derived dendritic cells(BMDCs)and induce their maturation and antigen cross-presentation.To avoid immune checkpoint molecule-induced T cell dysfunction,the immune checkpoint inhibitor,the anti-PD-L1 antibody,was introduced to boost tumor immunotherapy through a combination with the DBE@CCNPs nanovaccine.This combination therapy strategy can significantly alleviate tumor growth and may open up a potential strategy for clinical tumor immunotherapy.
基金The authors are thankful to National Natural Science Foundation of China(Nos.51925305,51873208,51833010,and 52203183)the National Key Research and Development Program of China(No.2021YFB3800900)the talent cultivation project Funds for the Innovation Laboratory for Sciences and Technologies of Energy Materials of Fujian Province(No.HRTP-[2022]52).
文摘As a revolutionary cancer treatment strategy,immunotherapy has attracted great attention.However,the effect of immunotherapy such as immune checkpoint blockade(ICB)is usually limited by insufficient immune response in the body.Herein,a polycation-based magnetic nanocluster platform was developed to load therapeutic nucleic acids,which could achieve gene therapy-mediated ICB and efficient magnetic hyperthermia therapy(MHT).The silencing of immune checkpoints together with MHT-induced immunogenic cell death(ICD)effectively alleviated the immune escape of cancer cells and significantly enhanced the visibility of cancer cells to the immune system.This combined treatment strategy activated a strong adaptive anti-cancer immune response in vivo,greatly inhibiting tumor growth,metastasis and recurrence.
基金This work was financially supported by the National Key R&D Program of China(2021YFB3800900)National Natural Science Foundation of China(51925305,51873208,51833010,51803210,51973217)Jilin province science and technology development program(20200201075JC).
文摘The low objective response rates and severe side effects largely limit the clinical outcomes of immune checkpoint blockade(ICB)therapy.Here,a tumor“self-killing”therapy based on gene-guided OX40L anchoring to tumor cell membrane was reported to boost ICB therapy.We developed a highly efficient delivery system HA/PEI-KT(HKT)to co-deliver the OX40L plasmids and unmethylated CG-enriched oligodeoxynucleotide(CpG).On the one hand,CpG induced the expression of OX40 on T cells within tumors.On the other hand,OX40L plasmids achieved the OX40L anchoring on the tumor cell membrane to next promote T cells responses via OX40/OX40L axis.Such synergistic tumor“self-killing”strategy finally turned“cold”tumors to“hot”,to sensitize tumors to programmed cell death protein 1/programmed cell death ligand 1(PD-1/PD-L1)blockade therapy,and promoted an immune-mediated tumor regression in both B16F10 and 4T1 tumor models,with prevention of tumor recurrence and metastasis.To avoid the side effects,the gene-guided OX40L anchoring and PD-L1 silencing was proposed to replace the existing antibody therapy,which showed negligible toxicity in vivo.Our work provided a new possibility for tumor“self-killing”immunotherapy to treated various solid tumors.
基金supported by the National Natural Science Foundation of China (11621505, 11435002, 31671016)
文摘Precise nanomedicine has been extensively explored for efficient cancer imaging and targeted cancer therapy, as evidenced by a few breakthroughs in their preclinical and clinical explorations. Here, we demonstrate the recent advances of intelligent cancer nanomedicine, and discuss the comprehensive understanding of their structure-function relationship for smart and efficient cancer nanomedicine including various imaging and therapeutic applications, as well as nanotoxicity. In particular, a few emerging strategies that have advanced cancer nanomedicine are also highlighted as the emerging focus such as tumor imprisonment, supramolecular chemotherapy, and DNA nanorobot. The challenge and outlook of some scientific and engineering issues are also discussed in future development. We wish to highlight these new progress of precise nanomedicine with the ultimate goal to inspire more successful explorations of intelligent nanoparticles for future clinical translations.
基金The authors are thankful to the National Natural Science Foundation of China(Nos.51925305,51803210,51520105004,51873208,51973217 and 51833010)Jilin province science and technology development program(Nos.20200201075JC,20180414027GH)National Science and Technology Major Projects for Major New Drugs Innovation and Development(No.2018ZX09711003-012).
文摘Despite of the promising achievements of immune checkpoints blockade therapy(ICB) in the clinic,which was often limited by low objective responses and severe side effects.Herein,we explored a synergistic strategy to combine in situ vaccination and gene-mediated anti-PD therapy,which was generated by unmethylated cytosine-phosphate-guanine(CpG) and pshPD-L1 gene co-delivery.PEI worked as the delivery carrier to co-deliver the CpG and pshPD-L1 genes,the formed PDC(PEI/DNA/CpG)nanoparticles were further shielded by aldehyde modified polyethylene glycol(OHC-PEG-CHO) via pH responsive Schiff base reaction for OHC-PEG-CHO-PEI/DNA/CpG nanoparticles(P(PDC) NPs) prepa ration.All steps could be finished within 30 min.Such simple nanoparticles achieved the synergistic antitumor efficacy in B16 F10 tumor-bearing mice,and the amplified T cell responses,together with enhanced NK cells infiltration were observed after the combined treatments.In addition,the pH responsive delivery system reduced the side effects triggered by anti-PD therapy.The facile and effective combination strategy we presented here might provide a novel treatment for tumor inhibition.
基金the National Natural Science Foundation of China(No.51873208)the National Science and Technology Major Projects for Major New Drugs Innovation and Development(No.2018ZX09711003-012)National Program for Support of Top-notch Young Professionals,Jilin Province Science and Technology Development Program(No.20180414027GH)for financial support to this work。
文摘A novel amphiphilic cationic block copolymer polylysine-b-polyphenylalanine(PLL-b-PPhe)was synthesized and self-assembled into micelles in aqueous solution,then shielded with poly(glutamic acid)(marked as PG/PLL-b-PPhe)to codeliver gene and drug for combination cancer therapy.Here,doxorubicin(DOX)was selected to be loaded into PLL-b-PPhe micelles and the drug loading efficiency was 8.0%.The drug release studies revealed that the PLL-b-PPhe micelles were pH sensitive and the released DOX could reach to 53.0%,65.0%,72.0%at pH 7.4,6.8 and 5.0,respectively.In order to reduce positive charge and cytotoxicity of PLL-b-PPhe micelles,PG was used as shelding,simultaneously condensed with Bcl2 siRNA to form gene carrier system.Compared with PEI,PG/PLL-b-PPhe had excellent gene transfection efficiency,especially when the molar ratio of PLL to PPhe was 30:60 and the mixed mass ratio of PLL-b-PPhe to gene was 5:1.More importantly,DOX and Bcl2 siRNA gene codelivery system displayed remarkable cytotoxicity against B16 F10 cells.Confocal laser scanning microscopy(CLSM)and flow cytometry were used to characterize endocytosis of the codelivery system,and confirmed that both DOX and Bcl2 siRNA had been endocytosed into B16 F10 cells.The above results indicated that gene and drug codelivery was a promising strategy in future cancer therapy.
基金financially supported by the National Natural Science Foundation of China (51390484, 21474104, 51403205, 51503200 and 51520105004)National program for support of Top-notch young professionalsJilin province science and technology development program (20160204032GX, 20180414027GH)
文摘Nano-therapeutic approach for clinical implementation of tumors remains a longstanding challenge in the medical field. The main challenges are rapid clearance, offtarget effect and the limited role in the treatment of metastatic tumors. Toward this objective, a cell-mediated strategy by transporting photothermal reagents and CpG adjuvant within macrophage vehicles is performed. The photothermal reagents are constructed by conjugating of hyperbranched polyethyleimine（PEI） to golden nanorode（GNR） via S-Au bonds.GNR-PEI/CpG nanocomposites, formed via electrostatic interaction and displayed excellent near-infrared（NIR） photothermal performance, exhibit immense macrophage uptake and negligible cytotoxic effect, which is essential for the fabrication of GNR-PEI/CpG loaded macrophages. GNR-PEI/CpG loaded macrophages demonstrated admirable photothermal response in vitro. Benefited from the functionalization of the binding adhesion between macrophages and 4 T1 cells, GNR-PEI/CpG loaded macrophages significantly promoted tumor accumulation in vivo and dramatically enhanced the efficiency of photothermal cancer therapy. Moreover, the immune system is activated after photothermal therapy, which is mainly attributed to the generation of tumor specific antigens and CpG adjuvant in situ. Our findings provide a potential cell-mediated nanoplatform for tumor therapy by combination of near infrared photothermal therapy and immunotherapy.
基金This work was financially supported by the National Natural Science Foundation of China （Nos. 51222307, 51233004, 51390484, 21474104 and 51473029）, the Jilin Province Science and Technology Development Program （Nos. 20120306 and 20130521011JH）, and the Open Research Fund of the Key Laboratory of Advanced Technologies of Materials, Ministry of Education, Southwest Jiaotong University, Youth Innovation Promotion Association, CAS.
文摘Gold nanoparticles have seen unprecedented development in the biomedical field, particularly for cancer ther- apy. They have received extensive attention because of their easy preparation, functionalization, biocompatibility, non-cytotoxicity, and detectability. Functionalized gold nanoparticles can be applied in the fields of drug and gene delivery, photothermal therapy, and bioimaging. This review introduces methods for preparing various shapes of gold nanoparticles and describes their current applications in the field of cancer treatment. Moreover, the review presents the development routes and current issues of gold nanoparticles in clinical theranostics.
基金This work was supported by the National Natural Science Foundation of China(51925305,51873208,51973217,51520105004 and 51803210)National Science and Technology Major Projects for Major New Drugs Innovation and Development(2018ZX09711003-012)and Jilin Province Science and Technology Development Program(20180414027GH and 20200201075JC).
文摘Tumor nanovaccines have potential applications in the prevention and treatment of malignant tumors.However,it remains a longstanding challenge in exploiting efficient nanocarriers for inducing potent specifically cellular immune responses.Toward this objective,we herein explore an intensive tumor immunotherapeutic strategy by combining mannosylated nanovaccines and gene regulated PD-L1 blockade for immune stimulation and killing activity.Here,we fabricate a mannose modified PLL-RT(Man-PLL-RT)mediated nanovaccines with dendritic cells(DCs)targeting capacity.Man-PLL-RT is capable of co-encapsulating with antigen(ovalbumin,OVA)and adjuvant(unmethylated cytosine-phosphate-guanine,CpG)by electrostatic interaction.This positively charged Man-PLL-RT/OVA/CpG nanovaccines can facilitate the endocytosis,maturation and cross presentation in DCs.However,the nanovaccines arouse limited inhibition of tumor growth,which is mainly due to the immunosuppressed microenvironment of tumors.Combining tumor nanovaccines with gene regulated PD-L1 blockade leads to an obvious tumor remission in B16F10 melanoma bearing mice.The collaborative strategy provides essential insights to boost the benefits of tumor vaccines by regulating the checkpoint blockade with gene therapy.
基金supported by the National Natural Science Foundation of China(51503200,21474104,51233004,51520105004, 51390484)Jilin Province Science and Technology Development Program (20160204032GX)the National Program for Support of Top-notch Young Professionals
文摘In recent years,various carriers for gene delivery nave been developed for biomedical applications.Among all kinds of gene carriers,cationic polymeric carriers for delivery therapeutic gene as non-viral carriers have received growing interests due to their improved high transfection efficiency with the relative safety.In particular,the advancement of novel polymeric gene carriers has gained much progress in the development of effective anticancer therapy.Herein,this review focused on the development of cationic polymeric carriers for cancer therapy,including polyethylenimine(PEI),polyamidoamine(PAMAM) dendrimers,polylysine(PLL),chitosan and modified cationic polymers.And recent progresses in the development of novel polymeric carriers for gene delivery,such as targeted gene carriers,responsive gene carriers and multifunctional gene carriers,were summarized.Finally,the future perspectives in the development of novel polymeric carriers for delivery gene were presented.
基金supported by the National Key Research and Development Program of China(2021YFB3800900)the National Natural Science Foundation of China(51925305,51873208,51973217,51520105004,51803210)Jilin Province Science and Technology Development Program(20180414027GH,20200201075JC,20210509005RQ)。
文摘Obesity has become an important public problem that endangers human conditions and urgently needs to be solved. However,most weight-loss drugs on the market have little effect and are accompanied by adverse effects such as strokes and heart attacks.Here, we construct an adipocyte-targeting polypeptide-based gene carrier consisting of an adipocyte-targeting peptide and ptoluylsulfonyl arginine-modified polylysine(ATS-PLL-RT), which can specifically bind to the prohibitin of mature adipocytes.We further construct a short hairpin RNA(shRNA) to simultaneously silence fatty acid binding proteins 4 and 5(shFABP4/5).FABPs are molecular chaperones for fatty acid metabolism and storage in cells. Moreover, we introduce metformin for combined therapy. First, the metformin combination can effectively improve the efficiency of gene transfection. In addition, metformin itself has an alleviating effect on diet-induced obesity and relevant metabolic diseases. The combination treatment of obese mice with ATS-PLL-RT/shFABP4/5 and metformin achieves body weight reduction and metabolic recovery. This study provides a potentially effective strategy for the clinical treatment of obesity as well as mitigating obesity-induced metabolic syndromes.
基金supported by the National Natural Science Foundation of China(51925305,51873208,51520105004,51833010,51803210,51803014)the National Science and Technology Major Projects for Major New Drugs Innovation and Development(2018ZX09711003-012)Jilin Province Science and Technology Development Program(20180414027GH)。
文摘Covalent organic framework(COF)materials have great development value in the biomedical field.However,the huge size and poor dispersion of COF materials severely limit their application.Here we successfully prepared COF nanoparticles with uniform size and good dispersion under the assistance of microwave.By adding some cationic polymers or small amine molecules,the dispersibility of COF could be further improved and its surface charge also increased.The prepared cationic COF nanoparticles(CLZU NPs)had excellent gene transfection ability and good biocompatibility.Designing low-toxic and highefficiency gene carrier is an important mission in the field of gene therapy.This COF-based gene vector provides a new direction for gene carrier design.
基金financially supported by the National Natural Science Foundation of China(nos.51925305,51873208,51833010,51803210,and 52073278)the National Top-Notch Young Professionals Program for their financial support of this research.
文摘Currently,reactive oxygen species(ROS)generation primarily depends upon light and O2,which hampers its further biomedical application.Here,we report that amanganese(Ⅲ)salen-based complex(MnS)can continuously catalyze overexpressed hydrogen peroxide(H_(2)O_(2))in the tumor microenvironment to ^(1)O_(2),while the nanocarrier(MIL-100)as a Fenton reagent can convert H_(2)O_(2) to hydroxyl radicals(·OH)through the Fenton reaction,inducing noticeable intracellular DNA strand scission and lipid peroxidation to provoke tumor cell apoptosis without the involvement of light and O_(2).Moreover,MIL-100 depleted the antioxidant glutathione,further amplifying intracellular oxidative pressure,which in turn led to the self-degradation of MIL-100,suggesting the long-term biosafety of the nanoplatform.Owing to the excellent magnetic resonance imaging performance of MnS,the diagnosis and specific treatment of tumors were eventually achieved.This work provides a novel approach for the realization of effective tumor catalytic therapy independent of light and O_(2) and a promising reference for the development of a wide range of catalytic therapeutic agents.
基金supported by the National Key Research and Development Program of China(2021YFB3800900)National Natural Science Foundation of China(51925305,52173115,52073278)Research Foundation for Advanced Talents of Xiamen University of Technology(5010423019,YKJ22052R)。
文摘The complex and rapidly progressing nature of sepsis calls for the development of multifunctional and rapid-acting therapeutic agents,instead of single-modal treatments.To address this challenge,a biodegradable,easily synthesized,and antibiotic-free multifunctional nanoparticle has been created for sepsis therapy.The nanoparticle was formed by the electrostatic interaction between two endogenous small molecule-derived polymers,poly(lipoic acid)and poly-lysine,and possessed various functions such as antibacterial activity,adsorption of cell-free DNA,scavenging of reactive oxygen and nitrogen species,providing a comprehensive approach to combating sepsis.Treatment using the cecal ligation and puncture(CLP)model confirmed the therapeutic benefits of the nanoparticles,demonstrating reduced levels of reactive oxygen across multiple organs,diminished levels of M1 proinflammatory macrophages,and elevated levels of M2 anti-inflammatory macrophages post-treatment.These findings emphasized the effectiveness of the nanoparticles in sepsis therapy,and properties of degradation,easy preparation,and swift therapeutic response made them promising for the future clinical applications.
