The self-adjuvant heterocyclic lipid nanoparticles encapsulated with vaccine and STAT3 siRNA boost cancer immunotherapy through DLN-targeted and STING pathway

A great potential of tumor vaccine-based immunotherapy has been emerged; however, the low cross-presentation of tumor antigens, intrinsic immunosuppressive signaling of dendritic cells (DCs) and the immunosuppression in tumor microenvironment (TME) hindered the progress of tumor vaccine. In this article, approaches employed heterocyclic lipid nanoparticles (LNP) as a tumor vaccine and signal transduction and activator of transcription 3 (STAT3) siRNA carrier as well as a "self-adjuvant" by targeting draining lymph node (DLN) and stimulating stimulator of interferon genes (STING)-mediated type I interferon (IFN) innate immune response were proposed. Model antigens ovalbumin peptide 257-264 (OVA) were cross-presented to activate T cells; STAT3 siRNA acted synergistically with OVA to improve DCs maturation, enhance antigen presentation and abrogate immunosup-pressive TME; heterocyclic lipids induced the production of type I IFN via activating the STING pathway. Compared to DLin-MC3-DMA LNP, heterocyclic LNPs, especially A18-LNP, targeted DLN, delivered much OVA and STAT3 siRNA into cytoplasm of antigen-presenting cells (APCs, mainly DCs), activated STING pathway, promoted DCs maturation and antigen presentation, abrogated immunosuppression in TME, therefore, leading to robust anti-cancer response. Thus, heterocyclic LNPs efficiently delivered tumor vaccine and STAT3 siRNA and simultaneously activated the immune system through DLN-targeted and STING pathway, provided better anti-tumor effects, suggesting a promising strategy for cancer immunotherapy.