circNCX1-nanogel mitigates radiation-induced heart disease.

Radiation-induced heart disease (RIHD) is a significant late complication of radiotherapy for thoracic malignancies, limiting cancer control and patient well-being. Although RIHD has been extensively studied, its precise molecular mechanisms remain poorly defined, and effective therapeutic agents are lacking. Herein, we demonstrate that circNCX1, a circular RNA of SLC8A1 that regulates cytoplasmic calcium levels and muscle excitation-contraction coupling, was inhibited by radiation. To investigate this in vitro, human cardiomyocyte AC16 cells exposed to 4 Gy X-ray irradiation were used as a model. In irradiated AC16 cells, circNCX1 functions as a miR-133a-3p-sequestering competing endogenous RNA (ceRNA) that derepresses PIK3C2A, thereby augmenting PI3K/AKT/mTOR signaling and limiting radiation-induced apoptosis. Building upon this observation, a cardiac-targeted circNCX1-nanogel is assembled by incorporating circNCX1 expression plasmid into a polyethylene glycol-sodium alginate (SA) nanogel matrix, and subsequently modified with targeting PCM and TAT peptides to augment cardiac accumulation. For the in vivo study, male C57BL/6J mice receiving a single localized 20 Gy heart dose were used as a model for evaluating RIHD for 12 weeks. Intravenously administered circNCX1 nanogel rapidly accumulated in the heart prior to irradiation and conferred robust cardiac protection, evidenced by preserved cardiac function and reduced myocardial fibrosis and apoptosis. Histological analyses and serum biochemical markers of major organs demonstrated undetectable off-target injury. Collectively, these findings demonstrate that circNCX1 nanogel, particularly when administered prior to radiation, mitigates RIHD by improving ventricular function, reducing myocardial fibrosis and cardiomyocyte apoptosis, and reactivating the PI3K/AKT/mTOR survival pathway.