Self-Replicating mRNA Therapeutics on Cancer Immunotherapy-“Multifunctional Oncolytic Nanoparticles Deliver Self-Replicating IL-12 RNA to Eliminate Established Tumors and Prime Systemic Immunity”

mRNA vaccines against COVID-19 pandemic by Pfizer and Moderna saved and are saving millions of lives. The applications of mRNA therapeutics are also of great interest for cancer immunotherapy. Though therapies that synergistically stimulate immunogenic cancer cell death (ICD), inflammation and immune priming are important directions for cancer immunotherapy. However, even multi-agent therapies often fail to trigger all of the steps necessary for self-sustaining antitumor immunity. Here we describe self-replicating RNAs (replicon) encapsulated in lipid nanoparticles (LNP), which combine three key elements to engineer the tumor as “non-self” and manipulate the immune responses to reject the “non-self” tumor: (1) an LNP composition that potently promotes ICD, (2) RNA that stimulates danger sensors in transfected cells and (3) RNA-encoded interleukin (IL)-12 for modulation of immune cells. Intratumoral administration of LNP-replicons led to high-level expression of IL-12, stimulation of a type I interferon response and cancer cell ICD, resulting in a highly inflamed tumor microenvironment and priming of systemic antitumor immunity. In several mouse models of cancer, a single intratumoral injection of LNP-replicons eradicated large established tumors, induced protective immune memory and enabled regression of distal uninjected tumors. LNP-replicons, a kind of mRNA therapeutics, are thus a promising multifunctional single-agent immunotherapeutic.