Figure 6.

Most common innate pathways shown to be activated upon NANPs internalization. (A) Intracellular delivery of NANPs requires carriers; naked NANPs are immunoquiescent due to their ineffective crossing of biological membranes. Delivery of RNA rings and cubes trigger the immune system through TLR7. By-passing of TLR sensing can be compensated by RIG-I that can detect RNA NANPs bearing 5’ triphosphates. DNA containing NANPs can be sensed after promoter independent transcription of NANPs strands by RNA pol III. DNA fibers stimulate cellular immunity through cGAS-cGAMP-STING pathway. Additionally, interdependent DNA/RNA fiber NANPs can be rationally designed to release of RNAi inducers and NF-κB decoys upon their intracellular re-association. This results in gene specific silencing while simultaneously blocking NF-kB translocation to nucleus thus lowering the proinflammatory immune responses. (B) Some of the architectural and compositional parameters that define immunorecognition of NANPs.