Ultrasound-responsive biomimetic nanocarrier triggers spatiotemporal PROTAC release and ROS storm to disrupt TNBC immunosuppression via coordinated apoptosis/ferroptosis/senescence activation

Triple-negative breast cancer (TNBC) poses significant therapeutic challenges due to its aggressive metastasis and immunosuppressive microenvironment. Herein, we developed a tumor-targeting biomimetic nanosystem (MTB@LM) integrating BRD4-targeting PROTAC (dBET6), Mn-TCPP-based sonosensitizers, and a tumor cell membrane-fusogenic liposome hybrid membrane coating. MTB@LM efficiently accumulates in tumors via homologous targeting and bypasses lysosomal degradation through membrane fusion-mediated delivery. Under ultrasound activation, the nanosystem triggers a multimodal cascade: (1) Mn-enhanced sonodynamic therapy (SDT) amplifies ROS to overcome hypoxia/GSH resistance; (2) BRD4 degradation synergizes with SDT to induce apoptosis, while concurrent ferroptosis (via lipid peroxidation) and senescence (via p21/p16 activation) amplify immunogenic cell death (ICD); (3) Senescent tumor cells are eliminated by αPD-L1 to block immune evasion. In orthotopic 4T1 models, MTB@LM + US achieved > 85% tumor suppression and remodeled the immunosuppressive microenvironment by promoting dendritic cell maturation, CD8⁺ T cell infiltration, and M1 macrophage repolarization. Combining MTB@LM with αPD-L1 synergistically inhibited lung metastasis (> 90%) and established durable immune memory against recurrence. This nanotechnology-driven strategy integrates PROTAC delivery, SDT-amplified ICD, and senolytic immunotherapy, offering a promising paradigm for combating metastatic TNBC.