Activatable biomimetic raspberry-like nanoplatform enabled robust cascade therapy via spatiotemporal regulation of tumor immunogenicity and immunosuppression

Smart nanomedicine capable of stimulating the immunity cycle and synchronously modulating the tumor immunosuppressive microenvironment is highly desirable for treatment of malignant solid tumor. Herein, an activable biomimetic raspberry like nanoplatform (abbreviated as RCuS@tMCP) was created for photothermal cascade immunotherapy by the spatiotemporal control of immunogenic tumor cell death (ICD) and tumor associated macrophages (TAMs) reprogramming. RCuS@tMCP was developed by conjugating the second near-infrared (NIR-II) photothermal agent copper sulfide nanoparticles (CuS NPs) as the "raspberry seeds" on the surface of biomimic CpG/protamine immunocore (denoted as tMCP) through matrix metalloproteinase-2 cleavable peptide. In the tumor microenvironment, RCuS@tMCP enzymatically unlocked the small sized RGDK peptide modified CuS NPs (ca.12 nm), which penetrated deeply and specifically to αvβ3 overexpressed tumor cells and elicited in situ ICD under NIR-II laser irradiation, thus triggering an effective antitumor immune response. Meanwhile, the remaining tMCP precisely recognized TAMs under the guidance of M2 peptide and reeducated them to tumoricidal ones, thereby boosted the power of cytotoxic T lymphocytes. By the spatiotemporal cooperation, RCuS@tMCP significantly inhibited the tumor growth of both primary and distant 4T1 tumors and prevented malignant metastasis as demonstrated both in vitro and in vivo data. This study provides an appealing and intelligent therapeutic toolbox for efficient immunological cascade therapy.