Tumor‐Associated Macrophage and Tumor‐Cell Dually Transfecting Polyplexes for Efficient Interleukin‐12 Cancer Gene Therapy

Abstract Interleukin 12 (IL12) is a potent pro‐inflammatory chemokine with multifunction, including promoting cytotoxic T‐cell‐mediated killing of cancer cells. IL12‐based cancer gene therapy can overcome IL12's life‐threatening adverse effects, but its clinical translation has been limited by the lack of systemic gene‐delivery vectors capable of efficiently transfecting tumors to produce sufficient local IL12. Macrophages inherently excrete IL12, and tumor‐associated macrophages (TAMs) are the major tumor component taking up a large fraction of the vectors arriving in the tumor. It is thus hypothesized that a gene vector efficiently transfecting both cancer cells and TAMs would make the tumor to produce sufficient IL12; however, gene transfection of TAMs is challenging due to their inherent strong degradation ability. Herein, an IL12 gene‐delivery vector is designed that efficiently transfects both cancer cells and TAMs to make them as a factory for IL12 production, which efficiently activates anticancer immune responses and remodels the tumor microenvironment, for instance, increasing the M1/M2 ratio by more than fourfold. Therefore, the intravenously administered vector retards tumor growth and doubles survival in three animal models’ with negligible systemic toxicities. This work reports the first nonviral IL12 gene delivery system that effectively makes use of both macrophages and tumor cells.