Intracellular Self‐Assembly Driven Nucleus‐Targeted Photo‐Immune Stimulator with Chromatin Decompaction Function for Robust Innate and Adaptive Antitumor Immunity

Abstract Efficient nuclear DNA damage and release is highly recommended to improve the photodynamic immunotherapy by eliciting innate immune response yet remains challenging. Herein, an intracellular self‐assembly driven nucleus‐targeted photo‐immune stimulator (PIS) with chromatin decompaction function is reported for innate and adaptive antitumor immunity co‐activation. The PIS consists of vorinostat (SAHA)‐loaded manganese‐porphyrin metal‐organic framework (Mn (III)‐TCPP MOF) with further modification of AS1411 aptamer. The PIS can be efficiently internalized by tumor cells and disassembled under the intracellular overexpressed glutathione (GSH). Notably, the released AS1411 is able to be self‐assembled with photosensitizer TCPP in situ within cells, driving nucleus‐targeted delivery of TCPP; meanwhile, the loaded SAHA can induce chromatin decompaction, cooperatively promoting TCPP‐mediated photodynamic nuclear DNA damage and cytosolic release under laser irradiation. In addition, the released manganese ions (Mn 2+ ) further enhance the cytosolic DNA/cyclic GMP‐AMP synthase (cGAS)‐stimulator of interferon gene (STING) pathway mediated innate immunity, which synergizes with PDT‐induced immunogenic cell death to achieve co‐activation of innate and adaptive immunity. Compared to traditional PDT, the self‐assembly driven nucleus‐targeted PDT system with chromatin decompaction show significantly enhanced efficacy for inhibiting primary tumor growth and distant metastasis in several xenograft tumor models, mechanistically by promoting the maturation of dendritic cells and tumor infiltration of natural killer cell, cytotoxic T lymphocytes.