Osteoporosis is majorly caused by an imbalance between osteoclastic and osteogenic niches. Despite thedevelopment of nationally recognized first-line anti-osteoporosis drugs, including alendronate (AL), their lowbioav...Osteoporosis is majorly caused by an imbalance between osteoclastic and osteogenic niches. Despite thedevelopment of nationally recognized first-line anti-osteoporosis drugs, including alendronate (AL), their lowbioavailability, poor uptake rate, and dose-related side effects present significant challenges in treatment. Thiscalls for an urgent need for more effective bone-affinity drug delivery systems. In this study, we produced hybridstructures with bioactive components and stable fluffy topological morphology by cross-linking calcium andphosphorus precursors based on mesoporous silica to fabricate nanoadjuvants for AL delivery. The subsequentgrafting of -PEG-DAsp8 ensured superior biocompatibility and bone targeting capacity. RNA sequencing revealedthat these fluffy nanoadjuvants effectively activated adhesion pathways through CARD11 and CD34 molecularmechanisms, hence promoting cellular uptake and intracellular delivery of AL. Experiments showed that smalldoseAL nanoadjuvants effectively suppress osteoclast formation and potentially promote osteogenesis. In vivoresults restored the balance between osteogenic and osteoclastic niches against osteoporosis as well as theconsequent significant recovery of bone mass. Therefore, this study constructed a drug nanoadjuvant withpeculiar topological structures and high bone targeting capacities, efficient intracellular drug delivery as well asbone bioactivity. This provides a novel perspective on drug delivery for osteoporosis and treatment strategies forother bone diseases.展开更多
This study presents an approach to enhanced cancer immunotherapy through the in situ synthesis of potassium permanganate(KMnO_(4))derived manganese dioxide(MnO_(2))micro/nano-adjuvants.Addressing the limitations of tr...This study presents an approach to enhanced cancer immunotherapy through the in situ synthesis of potassium permanganate(KMnO_(4))derived manganese dioxide(MnO_(2))micro/nano-adjuvants.Addressing the limitations of traditional immunotherapy due to patient variability and the complexity of the tumor microenvironment,our research establishes KMnO_(4)as a potent immunomodulator that enhances the efficacy of anti-programmed death-ligand 1(αPD-L1)antibodies.The in situ synthesized MnO_(2)adjuvants in the tumor exhibit direct interactions with biological systems,leading to the reduction of MnO_(2)to Mn^(2+)within the tumor,and thereby improving the microenvironment for immune cell activity.Our in vitro and in vivo models demonstrate KMnO_(4)’s capability to induce concentration-dependent cytotoxicity in tumor cells,triggering DNA damage and apoptosis.It also potentiates immunogenic cell death by upregulating calreticulin and high mobility group box 1(HMGB1)on the cell surface.The combination of KMnO_(4)withαPD-L1 antibodies substantially inhibits tumor growth,promotes dendritic cell maturation,and enhances CD8^(+)T cell infiltration,resulting in a significant phenotypic shift in tumor-associated macrophages towards a pro-inflammatory M1 profile.Our findings advocate for further research into the long-term efficacy of KMnO_(4)and its application in diverse tumor models,emphasizing its potential to redefine immune checkpoint blockade therapy and offering a new vista in the fight against cancer.展开更多
The chirality of bioactive molecules is closely related to their functions.D-amino acids commonly distributed in the bacterial cell walls trigger a robust anti-infective immune response.Inspired by that,two kinds of c...The chirality of bioactive molecules is closely related to their functions.D-amino acids commonly distributed in the bacterial cell walls trigger a robust anti-infective immune response.Inspired by that,two kinds of chiral polypeptides,poly(L-phenylalanine)-block-poly(L-lysine)(PL-K)and poly(Lphenylalanine)-block-poly(D-lysine)(PD-K),were synthesized and used as nanoadjuvants of nanovaccines for cancer prevention and therapy.The amphiphilic polypeptides self-assembled into nanoparticles with a diameter of about 30 nm during ultrasonic-assisted dissolution in phosphate-buffered saline.The nanovaccines PL-K-OVA and PD-K-OVA were easily prepared by mixing solutions of PL-K or PD-K and the model antigen chicken ovalbumin(OVA),respectively,with loading efficiencies of almost 100%.Compared to PL-K-OVA,PD-K-OVA more robustly induced dendritic cell maturation,antigen cross-presentation,and adaptive immune response.More importantly,it effectively prevented and treated the OVA-expressed B16-OVA melanoma model.PD-K-OVA achieved a tumor inhibition rate of 94.9%and even 97.0%by combining with anti-PD-1 antibody.Therefore,the chiral polypeptide nanoparticles represent simple,efficient,and extensively applicable nanoadjuvants for various nanovaccines.展开更多
Chiral materials with the same atomic compositions exhibit different chemical,physical,and biological properties because of their distinct spatial structures.Herein,a chiral strategy was proposed to develop poly(lacti...Chiral materials with the same atomic compositions exhibit different chemical,physical,and biological properties because of their distinct spatial structures.Herein,a chiral strategy was proposed to develop poly(lactic acid)(PLA)nanoparticle as an efficient nanoadjuvant to activate adaptive anticancer immunity.Two chiral nanovaccines were prepared by directly mixing amino-terminated PLA(PLLA-NH2 or PDLA-NH2)with the model protein antigen ovalbumin(OVA).After being injected into mice subcutaneously,both nanovaccines efficiently migrated to the lymph nodes to initiate the sequential anticancer immune responses.Compared with the PLLA nanovaccine(PLLA-OVA),the PDLA one(PDLA-OVA)contributed to more robust dendritic cell(DC)maturation,antigen presentation,and T lymphocyte activation.In addition to the activation of cellular immunity,PDLA-OVA also triggered a more vigorous activation of humoral immunity,which induced the production of more anti-OVA immunoglobulin G(IgG)than PLLA-OVA.When used as prophylactic or therapeutic nanovaccine toward murine melanoma models,PDLA-OVA triggered more potent adaptive anticancer immune responses that more effectively inhibited the cancer genesis and progression,indicating the significant potential of immunologically effective PDLA nanoadjuvant in cancer immunotherapy.展开更多
基金National Natural Science Foundation of China 82172233(X.Y.)Shanghai Baoshan District Science and Technology Commission medical health project 21-E-52(B.F.).
文摘Osteoporosis is majorly caused by an imbalance between osteoclastic and osteogenic niches. Despite thedevelopment of nationally recognized first-line anti-osteoporosis drugs, including alendronate (AL), their lowbioavailability, poor uptake rate, and dose-related side effects present significant challenges in treatment. Thiscalls for an urgent need for more effective bone-affinity drug delivery systems. In this study, we produced hybridstructures with bioactive components and stable fluffy topological morphology by cross-linking calcium andphosphorus precursors based on mesoporous silica to fabricate nanoadjuvants for AL delivery. The subsequentgrafting of -PEG-DAsp8 ensured superior biocompatibility and bone targeting capacity. RNA sequencing revealedthat these fluffy nanoadjuvants effectively activated adhesion pathways through CARD11 and CD34 molecularmechanisms, hence promoting cellular uptake and intracellular delivery of AL. Experiments showed that smalldoseAL nanoadjuvants effectively suppress osteoclast formation and potentially promote osteogenesis. In vivoresults restored the balance between osteogenic and osteoclastic niches against osteoporosis as well as theconsequent significant recovery of bone mass. Therefore, this study constructed a drug nanoadjuvant withpeculiar topological structures and high bone targeting capacities, efficient intracellular drug delivery as well asbone bioactivity. This provides a novel perspective on drug delivery for osteoporosis and treatment strategies forother bone diseases.
基金supported by the Natural Science Foundation of Guangdong Province(No.2023A1515030291)the Dongguan Science and Technology of Social Development Program(No.20211800905282)+8 种基金the National Key Research and Development Program of China(Nos.2022YFC2303600,2020YFA0908000)the Innovation Team and Talents Cultivation Program of National Administration of Traditional Chinese Medicine(No.ZYYCXTDC-202002)the CACMS Innovation Fund(Nos.CI2023E002,CI2021A05101,CI2021A05104)the Scientific and Technological Innovation Project of China Academy of Chinese Medical Sciences(Nos.CI2023D003,CI2021B014)the Science and Technology Foundation of Shenzhen(No.JCYJ20210324115800001)the Science and Technology Foundation of Shenzhen(Shenzhen Clinical Medical Research Center for Geriatric Diseases)the Shenzhen Medical Research Fund(No.B2302051)the Distinguished Expert Project of Sichuan Province Tianfu Scholar(No.CW202002)Shenzhen Science and Technology Program(No.RCBS20210609104424065).
文摘This study presents an approach to enhanced cancer immunotherapy through the in situ synthesis of potassium permanganate(KMnO_(4))derived manganese dioxide(MnO_(2))micro/nano-adjuvants.Addressing the limitations of traditional immunotherapy due to patient variability and the complexity of the tumor microenvironment,our research establishes KMnO_(4)as a potent immunomodulator that enhances the efficacy of anti-programmed death-ligand 1(αPD-L1)antibodies.The in situ synthesized MnO_(2)adjuvants in the tumor exhibit direct interactions with biological systems,leading to the reduction of MnO_(2)to Mn^(2+)within the tumor,and thereby improving the microenvironment for immune cell activity.Our in vitro and in vivo models demonstrate KMnO_(4)’s capability to induce concentration-dependent cytotoxicity in tumor cells,triggering DNA damage and apoptosis.It also potentiates immunogenic cell death by upregulating calreticulin and high mobility group box 1(HMGB1)on the cell surface.The combination of KMnO_(4)withαPD-L1 antibodies substantially inhibits tumor growth,promotes dendritic cell maturation,and enhances CD8^(+)T cell infiltration,resulting in a significant phenotypic shift in tumor-associated macrophages towards a pro-inflammatory M1 profile.Our findings advocate for further research into the long-term efficacy of KMnO_(4)and its application in diverse tumor models,emphasizing its potential to redefine immune checkpoint blockade therapy and offering a new vista in the fight against cancer.
基金supported by the National Key Research and Development Program(2022YFC2603500,2022YFC2603501,2021YFC2400600,2021YFC2400603,and 2021YFC2400604)the National Natural Science Foundation of China(52273158,52273159,U21A2099,52022095,and 52073280)+2 种基金the Science and Technology Development Program of Jilin Province(20210509005RQ,20210504001GH,20200404182YY,and 20200201322JC)the Special Project for City-Academy Scientific and Technological Innovation Cooperation of Changchun(21SH14)the Youth Innovation Promotion Association of Chinese Academy of Sciences(2019230).
文摘The chirality of bioactive molecules is closely related to their functions.D-amino acids commonly distributed in the bacterial cell walls trigger a robust anti-infective immune response.Inspired by that,two kinds of chiral polypeptides,poly(L-phenylalanine)-block-poly(L-lysine)(PL-K)and poly(Lphenylalanine)-block-poly(D-lysine)(PD-K),were synthesized and used as nanoadjuvants of nanovaccines for cancer prevention and therapy.The amphiphilic polypeptides self-assembled into nanoparticles with a diameter of about 30 nm during ultrasonic-assisted dissolution in phosphate-buffered saline.The nanovaccines PL-K-OVA and PD-K-OVA were easily prepared by mixing solutions of PL-K or PD-K and the model antigen chicken ovalbumin(OVA),respectively,with loading efficiencies of almost 100%.Compared to PL-K-OVA,PD-K-OVA more robustly induced dendritic cell maturation,antigen cross-presentation,and adaptive immune response.More importantly,it effectively prevented and treated the OVA-expressed B16-OVA melanoma model.PD-K-OVA achieved a tumor inhibition rate of 94.9%and even 97.0%by combining with anti-PD-1 antibody.Therefore,the chiral polypeptide nanoparticles represent simple,efficient,and extensively applicable nanoadjuvants for various nanovaccines.
基金supported by the National Natural Science Foundation of China(52273159,52273158,U21A2099,52173149,52073280,52022095,51973216,51873207,51833010)the Science and Technology Development Program of Jilin Province(20210509005RQ,20210504001GH,20200404182YY)+1 种基金the“Special Project for City-Academy Scientific and Technological Innovation Cooperation”of Changchun(21SH14)the Youth Innovation Promotion Association of Chinese Academy of Sciences(2019230)。
文摘Chiral materials with the same atomic compositions exhibit different chemical,physical,and biological properties because of their distinct spatial structures.Herein,a chiral strategy was proposed to develop poly(lactic acid)(PLA)nanoparticle as an efficient nanoadjuvant to activate adaptive anticancer immunity.Two chiral nanovaccines were prepared by directly mixing amino-terminated PLA(PLLA-NH2 or PDLA-NH2)with the model protein antigen ovalbumin(OVA).After being injected into mice subcutaneously,both nanovaccines efficiently migrated to the lymph nodes to initiate the sequential anticancer immune responses.Compared with the PLLA nanovaccine(PLLA-OVA),the PDLA one(PDLA-OVA)contributed to more robust dendritic cell(DC)maturation,antigen presentation,and T lymphocyte activation.In addition to the activation of cellular immunity,PDLA-OVA also triggered a more vigorous activation of humoral immunity,which induced the production of more anti-OVA immunoglobulin G(IgG)than PLLA-OVA.When used as prophylactic or therapeutic nanovaccine toward murine melanoma models,PDLA-OVA triggered more potent adaptive anticancer immune responses that more effectively inhibited the cancer genesis and progression,indicating the significant potential of immunologically effective PDLA nanoadjuvant in cancer immunotherapy.
