X-ray programmable interleukin-12 expression via a Ca²⁺ signaling-gated nanoplasmid system for cancer immunotherapy

Immunotherapy offers a promising opportunity for cancer treatment; while only a subset of patients derive substantial benefits because of its low response efficacy and potential off-target side effects. Unlike conventional immunotherapy, we herein report an X-ray programmable interleukin-12 (IL-12) expression via a calcium ion (Ca²⁺) signaling-gated nanoplasmid (SPN_CP) system for cancer immunotherapy. Such SPN_CP are designed to be destructible upon reactive oxygen species (ROS) respond, composing of a semiconducting polymer core as a radiosensitizer, transient receptor potential vanilloid 1 (TRPV1) agonist capsaicin and engineering plasmid containing Ca²⁺-responsive c-fos promoter and IL-12 as the target gene. SPN_CP are responded to produce ROS with low-dose X-ray activation by radiosensitization effect, which leads to the on-demand release of capsaicin and plasmid. As such, capsaicin turns on TRPV1 ion channel to facilitate extracellular Ca²⁺ influx and subsequent activation of MAPK/ERK signaling pathway. This signaling cascade then initiates the Ca²⁺-responsive c-fos promoter to drive IL-12 expression of the engineering plasmids, thereby allowing for potent IL-12-based immunotherapy. This X-ray programmable immunotherapy strategy shows obvious antitumor effects in TRPV1-positive orthotopic glioblastoma and metastatic breast cancer murine models. This current study highlights the potential and application of X-ray programmable immunotherapy strategy for renovating cancer treatments.