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

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Bioactive Materials 2023年第8期26卷 169-180页

作者： Ting Su Xiang Liu Shuibin Lin Furong Cheng Guizhi Zhu Center for Translational Medicine Precision Medicine InstituteThe First Affiliated HospitalSun Yat-sen UniversityGuangzhou510080China Department of Pharmaceutics and Center for Pharmaceutical Engineering and Sciences Institute for Structural Biology and Drug DiscoverySchool of PharmacyThe Developmental Therapeutics ProgramMassey Cancer CenterVirginia Commonwealth UniversityRichmondVA23298USA

Ionizable lipid nanocarriers have made historical contribution to COVID-19 mRNA ***,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 *** 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 *** 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 ***,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 *** 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 *** 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

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