Functional recovery of natural killer cell activity by nanoparticle‐mediated delivery of transforming growth factor beta 2 small interfering RNA

Natural killer (NK) cells are at the forefront of immunotherapies, as they have potent innate cytolytic effects on cancer cells. The success of NK cell therapies requires that they overcome immunosuppression in the tumor microenvironment. Tumors produce immunosuppressive factors like transforming growth factor beta (TGF‐β) that inhibit the effector functions of NK cells. Silencing of TGF‐beta signaling in NK cells is a potential approach to enhance their functions. However, transfection of NK cells by conventional methods is challenging. Here, we report the development of a nanoparticle (NP) system that delivers small interfering RNA for the TGF‐β receptor 2 (TGFBR2) into NK cells to restore their activation against cancer cells. Manganese dioxide NPs were synthesized by the reduction of potassium permanganate by poly (allylamine), which effectively complexed siRNA and protected it from degradation. The NPs were cytocompatible with NK cells and, upon loading with TGFBR2 siRNA, resulted in a 90% knockdown of the TGFBR2 receptor. NP‐mediated TGFBR2 receptor knockdown protected NK cells against TGF‐β suppression, which was studied in both two‐dimensional and three‐dimensional lung cancer cell culture systems. Namely, NK cells treated with TGFBR2 siRNA loaded NPs demonstrated higher interferon gamma production, infiltration, and killing of lung cancer cells compared with control NK cells. This study demonstrates the feasibility of NP‐mediated RNA interference in NK cells to increase their resilience to the immunosuppressive environments in solid tumors.