Cu–Mn Bimetallic Mesoporous Silica Nanosonosensitizers Enable Oxeiptosis-Mediated Sonodynamic Therapy for Ultra-Minimally Invasive Treatment of Benign Prostatic Hyperplasia

Benign prostatic hyperplasia (BPH) presents a significant clinical challenge, with conventional therapies carrying substantial risks, including urinary retention, sexual dysfunction, and prolonged recovery. To address the urgent need for safer, ultra-minimally invasive alternatives, we developed a sonosensitizing nanoplatform using copper-manganese-doped mesoporous silica nanoparticles (Cu-Mn@SiO₂) for ultrasound-induced sonodynamic therapy (SDT). Here, we demonstrate that this innovative strategy provides highly effective and precisely targeted therapy for BPH. In vitro studies revealed that Cu-Mn@SiO₂-mediated SDT significantly amplified intracellular reactive oxygen species (ROS) generation, triggering oxeiptosis characterized by PGAM5 cleavage, mitochondrial membrane depolarization, and mitochondrial damage in both BPH-1 epithelial and WPMY-1 stromal cells. In a testosterone-induced BPH rat model, a Cu-Mn@SiO₂-combined, localized SDT treatment resulted in a substantial 60% reduction in prostatic weight and a marked improvement in urinary function. Thermal imaging confirmed prostate-specific hyperthermia without affecting the surrounding tissues. Histopathology revealed reduced collagen deposition and restored glandular morphology with comprehensive biosafety assessments showing no systemic toxicity. By precisely inducing localized oxeiptosis within hyperplastic prostatic tissue via focused ultrasound activation, this Cu-Mn@SiO₂-based nanoplatform represents a clinically translatable, ultra-minimally invasive therapeutic strategy offering a superior safety profile for BPH management.