Immunotherapy has shown promising potential in cancer therapy;however, poor delivery by nanocarriers and insufficient immune response in tumors have severely impeded its clinical application. To overcome these disadva...Immunotherapy has shown promising potential in cancer therapy;however, poor delivery by nanocarriers and insufficient immune response in tumors have severely impeded its clinical application. To overcome these disadvantages, a site-specific and active transcellular drug delivery system was developed herein for chemotherapyenhanced immunotherapy. When arriving at the tumor site,the matrix metallopeptidase 2(MMP2)-responsive shell detached from the nanosystem, releasing positively charged cores. The cationic surface of the inner cores induced adsorption-meditated transcytosis, which facilitated transendothelial transportation and transcellular drug delivery into distal tumor cells. PD-L1 antibody and chemotherapeutic drugs were loaded in the outer layer and inner cores of the nanosystem, respectively, to be precisely delivered to target sites, thereby achieving synchronized delivery and siteoriented release of different anticancer agents. PD-L1 antibody released in the tumor microenvironment effectively blocked the binding of PD-L1 to its receptors on the T cell surface. Oxaliplatin and indoximod co-delivered in the cationic cores can induce immunogenic cell death and attenuate the immunosuppressive effect throughout the tumor tissues,recruiting a large amount of T cells and further enhancing the immunotherapy. The resulting synergistic antitumor response could not only efficiently inhibit the growth of primary tumors, but also help prevent metastasis of primary tumor to distant sites. This study offers a novel nano-enabled strategy for chemo-immunotherapy in immunosuppressive tumors.展开更多
基金supported by the National Natural Science Foundation of China (21874078 and 22074072)Taishan Young Scholar Program of Shandong Province (tsqn20161027)+2 种基金the Natural Science Foundation of Shandong Province (ZR2019BH032)the People’s Livelihood Science and Technology Project of Qingdao (166257nsh and 173378nsh)the First-Class Discipline Project of Shandong Province。
文摘Immunotherapy has shown promising potential in cancer therapy;however, poor delivery by nanocarriers and insufficient immune response in tumors have severely impeded its clinical application. To overcome these disadvantages, a site-specific and active transcellular drug delivery system was developed herein for chemotherapyenhanced immunotherapy. When arriving at the tumor site,the matrix metallopeptidase 2(MMP2)-responsive shell detached from the nanosystem, releasing positively charged cores. The cationic surface of the inner cores induced adsorption-meditated transcytosis, which facilitated transendothelial transportation and transcellular drug delivery into distal tumor cells. PD-L1 antibody and chemotherapeutic drugs were loaded in the outer layer and inner cores of the nanosystem, respectively, to be precisely delivered to target sites, thereby achieving synchronized delivery and siteoriented release of different anticancer agents. PD-L1 antibody released in the tumor microenvironment effectively blocked the binding of PD-L1 to its receptors on the T cell surface. Oxaliplatin and indoximod co-delivered in the cationic cores can induce immunogenic cell death and attenuate the immunosuppressive effect throughout the tumor tissues,recruiting a large amount of T cells and further enhancing the immunotherapy. The resulting synergistic antitumor response could not only efficiently inhibit the growth of primary tumors, but also help prevent metastasis of primary tumor to distant sites. This study offers a novel nano-enabled strategy for chemo-immunotherapy in immunosuppressive tumors.
