Dual-Functional Biomimetic Nanoprobes for PET Imaging-Guided Sonodynamic Therapy and Chemotherapy of Triple-Negative Breast Cancer.

Triple-negative breast cancer (TNBC), a highly aggressive subtype characterized by rapid invasion, metastatic propensity, and rising incidence, remains challenging due to the absence of targeted therapies. This study introduces a biomimetic nanoprobe coated with hybrid cell membranes (erythrocyte and tumor cell membranes) to enhance immune evasion, tumor targeting, and therapeutic efficacy. The nanoprobe encapsulates chlorin e6 (Ce6) for sonodynamic therapy (SDT) and tirapazamine (TPZ), a hypoxia-activated prodrug, to enable synergistic hypoxia-responsive chemotherapy. Synthesis and characterization of RBCm/4T1m@D-Ce6-TPZ confirm its ability to generate reactive oxygen species (ROS) under ultrasound activation and exert potent cytotoxicity in vitro. Safety evaluation reveals negligible toxicity without ultrasound stimulation. A "click chemistry" enabled pretargeting imaging strategy visualizes in vivo distribution of the biomimetic membrane components, validating immune evasion and tumor-specific accumulation. These findings enabled predictive modeling of therapeutic outcomes. In subsequent experiments, combination SDT/chemotherapy with RBCm/4T1m@D-Ce6-TPZ achieved superior tumor growth inhibition and prolonged survival in murine models compared to monotherapy or single-membrane-coated controls. Ultrasound activation further enhanced efficacy. Notably, treatment mitigated splenomegaly and normalized aberrant immune cell counts, underscoring the critical role of immunomodulation in TNBC management. Hybrid biomimetic nanoprobes can overcome key limitations of TNBC therapy, offering a promising platform for future clinical translation.