Programmed polymersomes with spatio-temporal delivery of antigen and dual-adjuvants for efficient dendritic cells-based cancer immunotherapy

摘要

Since antigen and adjuvant are rapid clearance in vivo,insufficient delivery to induce dendritic cells(DCs)maturation and cross-presentation,as well as limited migration efficiency of DCs to secondary lymph organs,greatly hinders the development of DCs-based immunotherapy.Herein,PCL-PEG-PCL polymersomes(PCEP-PS)as antigen and adjuvants delivery nanoplatforms(IMO-PS)were well-designed,which can electrostatically adsorb OVA antigen on the surface via DOTAP lipid and effectively encapsulate OVA antigen into the inner hydrophilic cavity to achieve both initial antigen exposure as well as slow and sustained antigen release,incorporate MPLA within the lipid layer to ligate with extracellular TLR4 of DCs as well as encapsulate IMQ in the hydrophobic membrane to ligate with intracellular TLR7/8 of DCs for activating synergistic immune responses via different signaling pathways.The IMO-PS significantly improved antigen uptake,promoted DCs maturation and cytokines production.DCs treated with IMO-PS could enhance migration into draining lymphoid nodes,and eventually induced antigen-specific CD8+and CD4+T cell responses and OVA-specific cytotoxic T lymphocyte(CTL)responses.Prophylactic vaccination of EG7-OVA tumor-bearing mice by IMO-PS+DCs significantly extended tumor-free time,effectively suppressed tumor growth,and greatly extended median survival time.The strategy may provide an effective nanoplatform for co-delivery antigen and dual-adjuvants in a spatio-temporally programmed manner for DC-based cancer immunotherapy.