Biomimetic Diselenide‐Sonosensitizer Nanoplatform for Enhanced Sonodynamic Therapy and In Situ Remodeling Immunosuppressive Microenvironment via Activating Innate and Adaptive Immunotherapy

Sonodynamic therapy (SDT), which is non-invasive and controllable has the potential to treat triple-negative breast cancer (TNBC). However, the hypoxia and immunosuppressive tumor microenvironment (TME) often block the production of reactive oxygen species and the induction of SDT-activated immunogenic cell death, thus limiting the activation of adaptive immune responses. To alleviate these challenges, we proposed the development of a multifunctional biomimetic nanoplatform (mTSeIR), which was designed with diselenide-conjugated sonosensitizers and tirapazamine (TPZ), encapsulated within M1 macrophage membrane. This nanoplatform utilized hypoxia-induced chemotherapy to improve the efficacy of SDT, to further enhance adaptive immunotherapy by activating innate immunity and remodeling the immunosuppressive TME. Firstly, the prodrug TPZ was activated due to the increased oxygen consumption associated with SDT. Subsequently, the mTSeIR enhanced repolarization of M2 macrophages to the M1 phenotype. The diselenide component in mTSeIR effectively activated the natural killer cell-mediated antitumor innate immune response. Ultimately, in vivo studies indicated that mTSeIR+US with good biosafety achieved over 98% tumor inhibition and enhanced adaptive immunotherapy. This research presents an efficient approach that addressed the limitations of SDT and achieves simultaneous activation of both innate and adaptive immunotherapy, resulting in significant antitumor and anti-metastatic efficacy in TNBC.