Acid-switchable nanoparticles induce self-adaptive aggregation for enhancing antitumor immunity of natural killer cells  

作　　者：Xiangshi Sun Xiaoxuan Xu Jue Wang Xinyue Zhang Zitong Zhao Xiaochen Liu Guanru Wang Lesheng Teng Xia Chen Dangge Wang Yaping Li 

机构地区：[1]Department of Pharmacology,College of Basic Medical Sciences,Jilin University,Changchun,130021,China [2]State Key Laboratory of Drug Research&Center of Pharmaceutics,Shanghai Institute of Materia Medica,Chinese Academy of Sciences,Shanghai 201203,China [3]Yantai Key Laboratory of Nanomedicine&Advanced Preparations,Yantai Institute of Materia Medica,Yantai,264000,China [4]School of Life Sciences,Jilin University,Changchun,130012,China [5]Shandong Laboratory of Yantai Drug Discovery,Bohai Rim Advanced Research Institute for Drug Discovery,Yantai,264000,China [6]School of Chinese Materia Medica,Nanjing University of Chinese Medicine,Nanjing,210023,China

出　　处：《Acta Pharmaceutica Sinica B》2023年第7期3093-3105,共13页药学学报（英文版）

基　　金：Financial supports from the National Natural Science Foundation of China(32170935,81903548,and31930066);the Youth Innovation Promotion Association of CAS(2019283,China);Shandong Provincial Natural Science Foundation(ZR2019PH013,China)are gratefully acknowledged。

摘　　要：Deficiency of natural killer(NK)cells shows a significant impact on tumor progression and failure of immunotherapy.It is highly desirable to boost NK cell immunity by upregulating active receptors and relieving the immunosuppressive tumor microenvironment.Unfortunately,mobilization of NK cells is hampered by poor accumulation and short retention of drugs in tumors,thus declining antitumor efficiency.Herein,we develop an acid-switchable nanoparticle with self-adaptive aggregation property for co-delivering galunisertib and interleukin 15(IL-15).The nanoparticles induce morphology switch by a decomposition-metal coordination cascade reaction,which provides a new methodology to trigger aggregation.It shows self-adaptive size-enlargement upon acidity,thus improving drug retention in tumor to over 120 h.The diameter of agglomerates is increased and drug release is effectively promoted following reduced p H values.The nanoparticles activate both NK cell and CD8+T cell immunity in vivo.It significantly suppresses CT26 tumor in immune-deficient BALB/c mice,and the efficiency is further improved in immunocompetent mice,indicating that the nanoparticles can not only boost innate NK cell immunity but also adaptive T cell immunity.The approach reported here provides an innovative strategy to improve drug retention in tumors,which will enhance cancer immunotherapy by boosting NK cells.

关 键 词：Nanoparticle AGGREGATION Drug retention Natural killer cells Cancer immunotherapy Acid-switchable Galunisertib IL-15 

分 类 号：R730.51[医药卫生—肿瘤]