Trimodal Sono/Photoinduced Focal Therapy for Localized Prostate Cancer: Single‐Drug‐Based Nanosensitizer under Dual‐Activation

Abstract Focal therapy, or partial gland ablation, represents the middle ground between active surveillance and definitive treatment strategies against localized prostate cancer (PCa), among which the ultrasound‐ and light‐mediated focal therapies are quite promising. Herein, for the first time in the literature, a novel polysaccharide‐based nanoprodrug is fabricated for synergistic sonodynamic therapy and phototherapy against localized PCa. Specifically, the cyanine dye IR806 is conjugated to chondroitin sulfate (CS) via disulfide linkages to obtain CS‐ss‐IR806 (CSR) conjugates, which then self‐assemble to form CSR nanoparticles (NPs) with properties of enhanced endocytosis, redox/hyaluronidase‐responsiveness, and mitochondria‐targeted ability. In contrast to free sensitizers, CSR NPs reveal dramatically enhanced water solubility, substantially lower dark toxicity, and superior biocompatibility. Encouragingly, favorable hyperthermia and high reactive oxygen species generation are observed on exposing CSR NPs to combined sono/photoirradiation. In a PCa tumor‐bearing mice model, intratumoral injection with a markedly low dose of CSR NPs followed by dual‐irradiation results in superior trimodal anticancer efficacy when compared with either monoirradiation strategy. Such synergistic antitumor efficacy is further demonstrated to be associated with the common and complementary mechanisms of sonotherapy and phototherapy. This work provides a promising approach as a next‐generation focal therapy strategy against localized PCa.