Chemotherapy remains one of the irreplaceable treatments for cancer therapy.The use of immunogenic cell death(ICD)-inducing chemotherapeutic drugs offers a practical strategy for killing cancer cells,simultaneously el...Chemotherapy remains one of the irreplaceable treatments for cancer therapy.The use of immunogenic cell death(ICD)-inducing chemotherapeutic drugs offers a practical strategy for killing cancer cells,simultaneously eliciting an antitumor immune response by promoting the recruitment of cytotoxic immune cells and production of granzyme B(GrB).However,numerous malignant cancers adaptively acquired the capacity of secreting serpinb9(Sb9),a physiological inhibitor of GrB,which can reversibly inhibit the biological activity of GrB.To circumvent this dilemma,in this study,an integrated tailor-made nanomedicine composed of tumor-targeting peptide(Arg-Gly-Asp,RGD)decorated liposome,doxorubicin(DOX,an effective ICD inducer),and the compound 3034(an inhibitor of Sb9),is developed(termed as D3RL)for breast cancer chemo-immunotherapy.In vitro and in vivo studies show that D3RL can directly kill tumor cells and trigger the host immune response by inducing ICD.Meanwhile,D3RL can competitively relieve the inhibition of Sb9 to GrB.The restored GrB can not only effectively induce tumor immunotherapy,but also degrade matrix components in the tumor microenvironment,consequently improving the infiltration of immune cells and the penetration of nanomedicines,which in return enhance the combined antitumor effect.Taken together,this work develops an integrated therapeutic solution for targeted production and restoration of GrB to achieve a combined chemo-immunotherapy for breast cancer.展开更多
Traditional surgical treatment is difficult to thoroughly remove esophageal squamous cell carcinomas(ESCC),postoperative recurrence caused by residual tumor cells is a critical factor in the poor prognosis.Since surgi...Traditional surgical treatment is difficult to thoroughly remove esophageal squamous cell carcinomas(ESCC),postoperative recurrence caused by residual tumor cells is a critical factor in the poor prognosis.Since surgical resection promotes the local angiogenesis at the tumor site,further exacerbating the proliferation and invasion of residual tumor cells,it is urgent to inhibit angiogenesis after surgery.Here,a functional peptide-based nanomedicine was obtained from peptide–drug conjugates,which are composed of a hydrophilic targeting motif(vascular endothelial growth factor family and their receptors(VEGFR)targeting peptide for anti-angiogenesis),an ester-linked hydrophobic oridonin(ORI).The nanomedicine exhibits esterase-catalyzed disassembly and drug release,significantly enhanced the anti-tumor efficacy of chemotherapeutics in a postoperative tumor recurrence model through synergistic anti-angiogenic strategies.This study provides an integrated solution for anti-angiogenesisaugmented chemotherapy and demonstrates the encouraging potential for postoperative treatment.展开更多
Nanocarriers with intrinsic immune adjuvant properties can activate the innate immune system while delivering tumor antigen,thus efficiently facilitating antitumor adaptive immunity.Bacteria-derived outer membrane ves...Nanocarriers with intrinsic immune adjuvant properties can activate the innate immune system while delivering tumor antigen,thus efficiently facilitating antitumor adaptive immunity.Bacteria-derived outer membrane vesicles(OMVs)are an excellent candidate due to their abundance of pathogen associated molecular patterns.However,during the uptake of OMVs by dendritic cells(DCs),the interaction between lipopolysaccharide and toll-like receptor 4 induces rapid DC maturation and uptake blockage,a phenomenon we refer to as“maturation-induced uptake obstruction"(MUO).Herein we decorated OMV with the DC-targeting aDEC205 antibody(OMV-DEC),which endowed the nanovaccine with an uptake mechanism termed as 4<not restricted to maturation via antibody modifying”(Normandy),thereby overcoming the MUO phenomenon.We also proved the applicability of this nanovaccine in identifying the human tumor neoantigens through rapid antigen display.In summary,this engineered OMV represents a powerful nanocarrier for personalized cancer vaccines,and this antibody modification strategy provides a reference to remodel the DC uptake pattern in nanocarrier design.展开更多
基金supported by grants from the National Natural Science Foundation of China(Nos.32000998,and 32201240)The Young Elite Scientists Sponsorship Program by Henan Association for Science and Technology(No.2022HYTP046)+2 种基金the China Postdoctoral Science Foundation(Nos.2019TQ0285,2019M662513,and 2021TQ0298)Henan provincial Medical Science and Technology Research Project(No.LHGJ20210210)Science and Technology Development Project of Henan Province(Nos.212102310138 and 222102310525).
文摘Chemotherapy remains one of the irreplaceable treatments for cancer therapy.The use of immunogenic cell death(ICD)-inducing chemotherapeutic drugs offers a practical strategy for killing cancer cells,simultaneously eliciting an antitumor immune response by promoting the recruitment of cytotoxic immune cells and production of granzyme B(GrB).However,numerous malignant cancers adaptively acquired the capacity of secreting serpinb9(Sb9),a physiological inhibitor of GrB,which can reversibly inhibit the biological activity of GrB.To circumvent this dilemma,in this study,an integrated tailor-made nanomedicine composed of tumor-targeting peptide(Arg-Gly-Asp,RGD)decorated liposome,doxorubicin(DOX,an effective ICD inducer),and the compound 3034(an inhibitor of Sb9),is developed(termed as D3RL)for breast cancer chemo-immunotherapy.In vitro and in vivo studies show that D3RL can directly kill tumor cells and trigger the host immune response by inducing ICD.Meanwhile,D3RL can competitively relieve the inhibition of Sb9 to GrB.The restored GrB can not only effectively induce tumor immunotherapy,but also degrade matrix components in the tumor microenvironment,consequently improving the infiltration of immune cells and the penetration of nanomedicines,which in return enhance the combined antitumor effect.Taken together,this work develops an integrated therapeutic solution for targeted production and restoration of GrB to achieve a combined chemo-immunotherapy for breast cancer.
基金the National Natural Science Foundation of China(Nos.32000998 and U2004123)the Young Elite Scientists Sponsorship Program by Henan Association for Science and Technology(No.2022HYTP046)the China Postdoctoral Science Foundation(Nos.2019TQ0285,2019M662513,2021TQ0298,and 2022TQ0296).
文摘Traditional surgical treatment is difficult to thoroughly remove esophageal squamous cell carcinomas(ESCC),postoperative recurrence caused by residual tumor cells is a critical factor in the poor prognosis.Since surgical resection promotes the local angiogenesis at the tumor site,further exacerbating the proliferation and invasion of residual tumor cells,it is urgent to inhibit angiogenesis after surgery.Here,a functional peptide-based nanomedicine was obtained from peptide–drug conjugates,which are composed of a hydrophilic targeting motif(vascular endothelial growth factor family and their receptors(VEGFR)targeting peptide for anti-angiogenesis),an ester-linked hydrophobic oridonin(ORI).The nanomedicine exhibits esterase-catalyzed disassembly and drug release,significantly enhanced the anti-tumor efficacy of chemotherapeutics in a postoperative tumor recurrence model through synergistic anti-angiogenic strategies.This study provides an integrated solution for anti-angiogenesisaugmented chemotherapy and demonstrates the encouraging potential for postoperative treatment.
基金the National Key R&D Program of China(Grants No.2018YFA0208900,2018YFE0205300,and 2021YFA0909900)the Strategic Priority Research Program of Chinese Academy of Sciences(Grant No.XDB36000000)+5 种基金the CAS Project for Young Scientists in Basic Research(Grant No.YSBR-010)the Beijing Natural Science Foundation of China(Grant No.Z200020)the Beijing Nova Program(Z201100006820031)the National Natural Science Foundation of China(Grants No.32171384,31800838,31820103004,31730032,and 51861145302)the Key Research Project of Frontier Science of the Chinese Academy of Sciences(Grant No.QYZDJ-SSW-SLH022)the Innovation Research Group of National Natural Science Foundation(Grant No.11621505).
文摘Nanocarriers with intrinsic immune adjuvant properties can activate the innate immune system while delivering tumor antigen,thus efficiently facilitating antitumor adaptive immunity.Bacteria-derived outer membrane vesicles(OMVs)are an excellent candidate due to their abundance of pathogen associated molecular patterns.However,during the uptake of OMVs by dendritic cells(DCs),the interaction between lipopolysaccharide and toll-like receptor 4 induces rapid DC maturation and uptake blockage,a phenomenon we refer to as“maturation-induced uptake obstruction"(MUO).Herein we decorated OMV with the DC-targeting aDEC205 antibody(OMV-DEC),which endowed the nanovaccine with an uptake mechanism termed as 4<not restricted to maturation via antibody modifying”(Normandy),thereby overcoming the MUO phenomenon.We also proved the applicability of this nanovaccine in identifying the human tumor neoantigens through rapid antigen display.In summary,this engineered OMV represents a powerful nanocarrier for personalized cancer vaccines,and this antibody modification strategy provides a reference to remodel the DC uptake pattern in nanocarrier design.