Calcium dysregulation in synergy with sonodynamic therapy via medroxyprogesterone-targeted and ROS-responsive nanoparticles for endometrial cancer

Effective therapies that enable precise drug delivery and integrated monitoring are urgently needed for fertility-sparing management of endometrial cancer (EC). Although calcium channel blockers (CCBs) exhibit anti-proliferative potential in EC, their poor tumor selectivity and systemic toxicity limit clinical translation. To overcome these limitations, a nanoparticle-mediated sonodynamic therapy (SDT) strategy is employed to deliver CCBs while integrating real-time imaging. This study develops MPA-RSP/Ce6/MDP, medroxyprogesterone (MPA)-modified nanoparticles based on a reactive oxygen species (ROS)-sensitive polymer (RSP), co-incorporating the sonosensitizer chlorin e6 (Ce6) and CCB manidipine (MDP). Upon ultrasound activation, Ce6 generates cytotoxic ROS, which trigger degradation of the ROS-responsive shell and release of MDP. The combination of ROS generation and calcium influx inhibition synergistically induces severe endoplasmic reticulum stress, thereby triggering immunogenic cell death and subsequent activation of antitumor immunity. This SDT approach further synergizes with PD-1 checkpoint inhibition, significantly enhancing therapeutic outcomes in vivo. Additionally, single-photon emission computed tomography (SPECT) imaging with co-assembled MPA-RSP/99mTc-RSP confirms efficient tumor accumulation. In summary, this study introduces an ultrasound-responsive nanoparticle that integrates calcium-homeostasis disruption, sonodynamic therapy, and immune activation for non-surgical treatment of endometrial cancer. This strategy shifts from sustained hormonal exposure to spatiotemporally controlled physical intervention, thereby establishing a multimodal foundation for EC fertility-preservation treatment.