Integrated spherical nucleic acid nanoreactor mobilizes targeted PD‐L1 proteolysis and cuproptosis for robust breast cancer immunotherapy

Abstract Cuproptosis‐oriented nanomedicine is highly appealing for cancer immunotherapy. However, its efficiency is greatly challenged by the complex biochemical and immunosuppressive environment. Herein, a pluripotent integrated spherical nucleic acid (SNA) nanoreactor was designed for targeted PD‐L1 degradation and chemo‐dynamically enhanced cuproptosis to synergically elicit robust immunotherapy against the triple‐negative breast cancer growth, recurrence and metastasis. The SNA nanoreactor (denoted as AMCuD ) was constructed by densely anchoring PD‐L1 aptamer around the biomimic nanocore of polydopamine‐cooper peroxide nanodots (CuO 2 NDs). Through the multivalent binding of aptamers to PD‐L1 on the surface of tumor cells, AMCuD promoted the lysosomal degradation of PD‐L1 and prevented its subcellular recycling to membrane. Simultaneously, CuO 2 NDs generate H 2 O 2 and Cu 2+ under acidic conditions, promoting the Fenton‐like reaction and disrupting the redox homeostasis, thus enhancing cuproptosis and immunogenic cell death, which activate an amplified antitumor immune response. Meanwhile, AMCuD targeted the immunosuppressive cells, especially tumor‐associated macrophages, and shaped them into immunostimulatory cells. Under the three‐pronged attack, AMCuD significantly inhibited the development of 4T1 orthotopic breast tumor and prevented its post‐surgery recurrence and malignant lung metastasis. This study provides a novel, integrated, and adjuvant‐free nanoplatform that combines protein‐targeted degradation and copper nanomedicine for highly efficient cuproptosis‐immunotherapy against solid tumors.