Ionizable polymeric nanocarriers for the codelivery of bi-adjuvant and neoantigens in combination tumor immunotherapy  

作　　者：Ting Su Xiang Liu Shuibin Lin Furong Cheng Guizhi Zhu 

机构地区：[1]Center for Translational Medicine,Precision Medicine Institute,The First Affiliated Hospital,Sun Yat-sen University,Guangzhou,510080,China [2]Department of Pharmaceutics and Center for Pharmaceutical Engineering and Sciences,Institute for Structural Biology and Drug Discovery,School of Pharmacy,The Developmental Therapeutics Program,Massey Cancer Center,Virginia Commonwealth University,Richmond,VA,23298,USA

出　　处：《Bioactive Materials》2023年第8期169-180,共12页生物活性材料（英文）

基　　金：G.Z.acknowledges funding support from NIH(R01CA266981,R01AI168684,R35GM143014,R21NS114455);DoD CDMRP Breast Cancer Breakthrough Award Level II(BC210931/P1);NIH-NCATS KL2 scholarship(KL2TR002648)via VCU C.Kenneth and Dianne Wright Center for Clinical and Translational Research(UL1TR002649);American Cancer Society Research Scholar Grant(RSG-22-055-01-IBCD);METAvivor Early Career Investigator Award,among others.The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.T.S.and F.C.acknowledge the National Natural Science Foundation of China(52103199,82102203);Guangdong Basic and Applied Basic Research Foundation(2020A1515110811).

摘　　要：Ionizable lipid nanocarriers have made historical contribution to COVID-19 mRNA vaccines.Here,we report ionizable polymeric nanoparticles that co-deliver bi-adjuvant and neoantigen peptides for cancer immunotherapy in combination with immune checkpoint blockade(ICB).Current cancer ICB benefits only a small subset of patients,largely due to a lack of pre-existing target cells and checkpoint targets for ICB,tumor antigenic heterogeneity,and tumor immunosuppression.Therapeutic vaccines hold the potential to enhance ICB therapeutic efficacy by expanding antitumor cell repertoires,upregulating immune checkpoint levels and hence sensitizing ICB,and reducing tumor immunosuppression.Chemically defined peptide vaccines are attractive,but their current therapeutic efficacy has been limited due to 1)poor vaccine delivery to immunomodulatory lymph nodes(LNs)and antigen(Ag)-presenting cells(APCs),2)poor immunostimulant adjuvant efficacy with restricted target cell subsets in humans,3)limited adjuvant/Ag codelivery to enhance Ag immunogenicity,and 4)limited ability to overcome tumor antigenic heterogeneity.Here,we developed nanovaccines(NVs)using pH-responsive polymeric micellular nanoparticles(NPs)for the codelivery of bi-adjuvant[Toll-like receptor(TLR)7/8 agonist R848 and TLR9 agonist CpG]and peptide neoantigens(neoAgs)to draining LNs for efficient Ag presentation in a broad range of APC subsets.These NVs potentiated the immunogenicity of peptide Ags and elicits robust antitumor T cell responses with memory,and remodeled the tumor immune milium with reduced tumor immunosuppression.As a result,NVs significantly enhanced ICB therapeutic efficacy for murine colorectal tumors and orthotopic glioblastoma multiforme(GBM).These results suggest marked potential of bi-adjuvant/neoAg-codelivering NVs for combination cancer immunotherapy.

关 键 词：Polymeric nanoparticles Combination adjuvants Cancer neoantigen Nanovaccine codelivery Cancer immunotherapy 

分 类 号：R730.51[医药卫生—肿瘤] TB383.1[医药卫生—临床医学]