Engineering hypoxia-specific core-shell nanotherapeutics: A sequential strategy for amplified multimodal synergistic breast cancer treatment.

The reactive oxygen species (ROS)-based chemodynamic therapy (CDT) and sonodynamic therapy (SDT) have garnered significant interests in advanced tumor treatments. However, their therapeutic efficacy is severely hindered by tumor hypoxia and overexpressed antioxidant glutathione (GSH) in the tumor microenvironment (TME). Motivated by the concept of metal coordination-based nanomedicine, we proposed an innovative strategy for synergistic tumor therapy tailored to the TME. Herein, we developed a multifunctional targeted delivery nanosystem based on the tirapazamine (TPZ)-loaded BT@M/T@T(Cu)GH cascade nanoreactor to enhance the synergistic efficacy of CDT, SDT, chemotherapy (CT) and starvation therapy (ST) against breast cancer. The rationally designed nanoreactor was constructed through covalent conjugation of glucose oxidase (GOx) onto TPZ-loaded BT@M/T@T(Cu) nanoparticles, wherein the formed tannic acid/copper (Ⅱ) (T(Cu)) network served as the "nanovalve"for BT@M/T nanoparticles. Surface functionalization with hyaluronic acid (HA) enabled BT@M/T@T(Cu) nanoparticles to effectively target CD44-overexpressed 4T1 breast tumors via passive targeting and active targeting effect, while mitigating cytotoxicity toward normal cells/tissues. Following successful tumor accumulation, BT@M/T@T(Cu)GH nanoparticles underwent pH-dependent disassembly and released TPZ, Cu and GOx, initiating a cascade of integrated therapeutic functions, including redox balance disruption, starvation, oxidative cytotoxicity, and hypoxia-activated chemotoxicity. When exposed to ultrasound (US) irradiation, BT@M/T@T(Cu)GH nanoparticles demonstrated sonosensitization capability, generating substantial singlet oxygen (O) through energy transfer processes. Owing to all these prominent features, the all-in-one nanomedicine exhibited significant apoptotic cell death and noteworthy tumor eradication in vivo, via synergistic combination of GOx-based ST, self-amplified CDT, hypoxia-activated CT, and US-activated SDT. Additionally, the administration of BT@M/T@T(Cu)GH had negligible effects on the normal growth. Taken together, this work establishes a versatile TiO-based nanosystem integrating tumor targeting and multi-mode synergistic therapy of breast cancer, offering a novel strategy for highly effective and precise treatment of malignancies.