The success of immunotherapy in pancreatic ductal adenocarcinoma(PDAC)is greatly limited by the scarcity of cytotoxic T lymphocytes(CTLs)in tumor microenvironment,which is mainly due to the physical barrier formed by ...The success of immunotherapy in pancreatic ductal adenocarcinoma(PDAC)is greatly limited by the scarcity of cytotoxic T lymphocytes(CTLs)in tumor microenvironment,which is mainly due to the physical barrier formed by a dense extracellular matrix(ECM).Here we reported a potent strategy to rectify the CTLs infiltration in PDAC by synergistically deactivating cancer-associated fibroblasts(CAFs)and driving T-Cell migration into tumor microenvironment.This combination therapy is achieved by co-delivery of vitamin D receptor ligand(calcipo-triol,Cal)and chemokine(CXCL9)using nanochaperone(nChap)delivery platform.We demonstrate that Cal reverses the activated CAFs to quiescence for resulting in a loosened ECM,while the CXCL9 gradient increases the recruitment signal of CD8+T cells,synergistically enhancing the intratumoral infiltration of CD8+T cells.Noteworthily,this system(Cal@nChap-CXCL9)promotes both the penetration of immunotherapeutic(anti-PD-1)and chemotherapeutic(gemcitabine),significantly enhancing the efficacy of chemo-immunotherapy for advanced large Panc02 tumors.This study provides a promising strategy for enhanced PDAC immunotherapy.展开更多
Natural molecular chaperones utilize spatially ordered multiple molecular forces to effectively regulate protein folding.However,synthesis of such molecules is a big challenge.The concept of“aggregate science”provid...Natural molecular chaperones utilize spatially ordered multiple molecular forces to effectively regulate protein folding.However,synthesis of such molecules is a big challenge.The concept of“aggregate science”provides insights to construct chemical entities(aggregates)beyond molecular levels to mimic both the structure and function of natural chaperone.Inspired by this concept,herein we fabricate a novel multi-interaction(i.e.,electrostatic and hydrophobic interaction)cooperative nanochaperone(multi-co-nChap)to regulating protein folding.This multi-co-nChap is fabricated by rationally introducing electrostatic interactions to the surface(corona)and confined hydrophobic microdomains(shell)of traditional single-hydrophobic interaction nanochaperone.We demonstrate that the corona electrostatic attraction facilitates the diffusion of clients into the hydrophobic microdomains,while the shell electrostatic interaction balances the capture and release of clients.By finely synergizing corona electrostatic attraction with shell electrostatic repulsion and hydrophobic interaction,the optimized multi-co-nChap effectively facilitated de novo folding of nascent polypeptides.Moreover,the synergy between corona electrostatic attraction,shell electrostatic attraction and shell hydrophobic interaction significantly enhanced the capability of multi-co-nChap to protect native proteins from denaturation at harsh temperatures.This work provides important insights for understanding and design of nanochaperone,which is a kind of ordered aggregate with chaperone-like activity that beyond the level of single molecule.展开更多
基金supported by National Natural Science Foundation of China(Grant Number:52373153,51933006,52293383)National Key Research and Development Program of China(Project number:2022YFA1205702)+1 种基金the Natural Science Foundation of Tianjin,China(Grant Number:24JCYBJC01830)Haihe Laboratory of Sus-tainable Chemical Transformations(Project number:YYJC202102).
文摘The success of immunotherapy in pancreatic ductal adenocarcinoma(PDAC)is greatly limited by the scarcity of cytotoxic T lymphocytes(CTLs)in tumor microenvironment,which is mainly due to the physical barrier formed by a dense extracellular matrix(ECM).Here we reported a potent strategy to rectify the CTLs infiltration in PDAC by synergistically deactivating cancer-associated fibroblasts(CAFs)and driving T-Cell migration into tumor microenvironment.This combination therapy is achieved by co-delivery of vitamin D receptor ligand(calcipo-triol,Cal)and chemokine(CXCL9)using nanochaperone(nChap)delivery platform.We demonstrate that Cal reverses the activated CAFs to quiescence for resulting in a loosened ECM,while the CXCL9 gradient increases the recruitment signal of CD8+T cells,synergistically enhancing the intratumoral infiltration of CD8+T cells.Noteworthily,this system(Cal@nChap-CXCL9)promotes both the penetration of immunotherapeutic(anti-PD-1)and chemotherapeutic(gemcitabine),significantly enhancing the efficacy of chemo-immunotherapy for advanced large Panc02 tumors.This study provides a promising strategy for enhanced PDAC immunotherapy.
基金National Natural Science Foundation of China,Grant/Award Numbers:51933006,52373153,52293383National Key Research and Development Program of China,Grant/Award Number:2022YFA1205702Haihe Laboratory of Sustainable Chemical Transformations,Grant/Award Number:YYJC202102。
文摘Natural molecular chaperones utilize spatially ordered multiple molecular forces to effectively regulate protein folding.However,synthesis of such molecules is a big challenge.The concept of“aggregate science”provides insights to construct chemical entities(aggregates)beyond molecular levels to mimic both the structure and function of natural chaperone.Inspired by this concept,herein we fabricate a novel multi-interaction(i.e.,electrostatic and hydrophobic interaction)cooperative nanochaperone(multi-co-nChap)to regulating protein folding.This multi-co-nChap is fabricated by rationally introducing electrostatic interactions to the surface(corona)and confined hydrophobic microdomains(shell)of traditional single-hydrophobic interaction nanochaperone.We demonstrate that the corona electrostatic attraction facilitates the diffusion of clients into the hydrophobic microdomains,while the shell electrostatic interaction balances the capture and release of clients.By finely synergizing corona electrostatic attraction with shell electrostatic repulsion and hydrophobic interaction,the optimized multi-co-nChap effectively facilitated de novo folding of nascent polypeptides.Moreover,the synergy between corona electrostatic attraction,shell electrostatic attraction and shell hydrophobic interaction significantly enhanced the capability of multi-co-nChap to protect native proteins from denaturation at harsh temperatures.This work provides important insights for understanding and design of nanochaperone,which is a kind of ordered aggregate with chaperone-like activity that beyond the level of single molecule.
