Scheme 1.

Schematic illustration of the design and therapeutic mechanism of the multifunctional nanoplatform NPs(3-MA/siNrf2/P-18) for enhanced SDT and immune activation. The nanoparticle co-encapsulates 3-MA, siNrf2, and P-18, and is administered intravenously for tumor-targeted delivery. In the reductive tumor microenvironment, intracellular glutathione triggers cleavage of disulfide bonds, facilitating controlled release of the payload. Upon US irradiation, P-18 generates ROS, inducing tumor cell apoptosis. Concurrent Nrf2 silencing attenuates antioxidant defenses, while 3-MA inhibits mitophagy, disrupting mitochondrial clearance and further amplifying intracellular ROS levels. This synergistic ROS accumulation promotes ICD, characterized by the release of DAMPs that enhance DCs maturation and antigen presentation. Additionally, 3-MA downregulates PD-L1 expression via NF-κB pathway inhibition, reversing T cell exhaustion and promoting robust CD8⁺ T cell-mediated cytotoxicity. Together, this strategy enhances SDT efficacy and elicits a potent anti-tumor adaptive immune response, offering a comprehensive approach for improved cancer therapy.