Sonodynamic therapy-boosted biomimetic nanoplatform targets ferroptosis and CD47 as vulnerabilities for cancer immunotherapy

The efficacy of cancer immunotherapy is frequently hindered by the immunosuppressive "cold" tumor microenvironment. Inducing immunogenic cell death (ICD) may address this limitation. Ferroptosis, a form of ICD characterized by iron-dependent lipid peroxidation, has gained attention as a therapeutic target due to its inherent or therapy-induced susceptibility in refractory cancers and resistant tumor microenvironments. CD47, overexpressed on tumor cell membranes, enables immune evasion by suppressing macrophage-mediated surveillance, positioning it as a promising immune checkpoint target for macrophage-driven immunotherapy. Combining ferroptosis induction with CD47 blockade represents a strategic approach to enhance therapeutic outcomes. In this study, we developed a biomimetic nanoplatform-IR780/MnO₂@PLGA@cell membrane-PEP20 nanoparticles-featuring a shell derived from 4T1 cell membranes conjugated with the CD47-inhibitory peptide PEP20. This design enables tumor-targeted delivery while enhancing macrophage phagocytosis of tumor cells. The MnO₂ core depletes intra-tumoral glutathione, downregulating glutathione peroxidase 4 and accumulating lipid peroxides to trigger ferroptosis. Concurrently, the ultrasound-responsive agent IR780 generates singlet oxygen under ultrasound irradiation, amplifying ferroptosis via oxidative stress. The resultant reactive oxygen species drive M2-to-M1 macrophage repolarization. Ferroptosis-mediated ICD further stimulates dendritic cell antigen presentation, activates cytotoxic T-cell immunity, and establishes durable immune memory. By exploiting tumor defense mechanisms as therapeutic vulnerabilities, this nanoplatform offers an innovative strategy for refractory cancer treatment.