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
Immunotherapy has great promise in improving malignant tumor treatment.However,the efficacy of existing strategies is often limited by the immunosuppressive environment.Here,we demonstrate an in situ bionic immunoacti...Immunotherapy has great promise in improving malignant tumor treatment.However,the efficacy of existing strategies is often limited by the immunosuppressive environment.Here,we demonstrate an in situ bionic immunoactivator,PLT-Bec1/DTA-1,with possessed natural advantages of platelets for tumor recruitment and activation,on which DTA-1(CD357 monoclonal antibody)and Bec1 were tethered as combined immune boosters.PLT-Bec1/DTA-1,as a self-triggered release repository,can deliver the pre-tethered Bec1 and DTA-1 deeply through the secretion of platelet microparticles(PMPs),thereby cooperate tacitly and exhibit superiority in immune activation of dendritic cells(DCs)and T cells via autophagy inducibility,coupled with glucocorticoid-induced tumor necrosis factor receptor(GITR)-triggered T_(Reg) suppression,remodeled the immunosuppressive network of tumor microenvironment.PLT-Bec1/DTA-1 promoted antigen presentation and T cell proliferation,and alleviated the low activity state of bone marrow-derived dendritic cells(BMDCs)in tumor suppressive environment.PLT-Bec1/DTA-1 inhibited tumor recurrence(5-and 13-fold lower of control group in tumor volume)and CD8^(+)T/T_(Reg) ratio(6.3-and 8.8-fold vs.control group)in mouse tumor model after intravenous or subcutaneous administration.Also,PLT-Bec1/DTA-1 prevented tumor colonization in lung through in situ immune activation,and was slightly superior to the combined of Bec1 and PD-L1.Our findings highlight the promise of delivering immunostimulatory payloads via bionic carriers,eliciting automatic in situ activation of effector immune cells in tumor microenvironment for tumor eradication.All these results provide promising prospects into the application of immunoactivator in improving cancer synergistic immunotherapy to overcome the bottlenecks in clinic.展开更多
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We would like to thank the National Natural Science Foundation of China(No.81973258)the Beijing Natural Science Foundation(Nos.L202044,7202092)for funding this work.
文摘Immunotherapy has great promise in improving malignant tumor treatment.However,the efficacy of existing strategies is often limited by the immunosuppressive environment.Here,we demonstrate an in situ bionic immunoactivator,PLT-Bec1/DTA-1,with possessed natural advantages of platelets for tumor recruitment and activation,on which DTA-1(CD357 monoclonal antibody)and Bec1 were tethered as combined immune boosters.PLT-Bec1/DTA-1,as a self-triggered release repository,can deliver the pre-tethered Bec1 and DTA-1 deeply through the secretion of platelet microparticles(PMPs),thereby cooperate tacitly and exhibit superiority in immune activation of dendritic cells(DCs)and T cells via autophagy inducibility,coupled with glucocorticoid-induced tumor necrosis factor receptor(GITR)-triggered T_(Reg) suppression,remodeled the immunosuppressive network of tumor microenvironment.PLT-Bec1/DTA-1 promoted antigen presentation and T cell proliferation,and alleviated the low activity state of bone marrow-derived dendritic cells(BMDCs)in tumor suppressive environment.PLT-Bec1/DTA-1 inhibited tumor recurrence(5-and 13-fold lower of control group in tumor volume)and CD8^(+)T/T_(Reg) ratio(6.3-and 8.8-fold vs.control group)in mouse tumor model after intravenous or subcutaneous administration.Also,PLT-Bec1/DTA-1 prevented tumor colonization in lung through in situ immune activation,and was slightly superior to the combined of Bec1 and PD-L1.Our findings highlight the promise of delivering immunostimulatory payloads via bionic carriers,eliciting automatic in situ activation of effector immune cells in tumor microenvironment for tumor eradication.All these results provide promising prospects into the application of immunoactivator in improving cancer synergistic immunotherapy to overcome the bottlenecks in clinic.
