A Tumor Environment‐Activated Photosensitized Biomimetic Nanoplatform for Precise Photodynamic Immunotherapy of Colon Cancer

Abstract Aggressive nature of colon cancer and current imprecise therapeutic scenarios simulate the development of precise and effective treatment strategies. To achieve this, a tumor environment‐activated photosensitized biomimetic nanoplatform (PEG₂₀₀₀‐SiNcTI‐Ph/CpG‐ZIF‐8@CM) is fabricated by encapsulating metal‐organic framework loaded with developed photosensitizer PEG₂₀₀₀‐SiNcTI‐Ph and immunoadjuvant CpG oligodeoxynucleotide within fusion cell membrane expressing programmed death protein 1 (PD‐1) and cluster of differentiation 47 (CD47). By stumbling across, systematic evaluation, and deciphering with quantum chemical calculations, a unique attribute of tumor environment (low pH plus high concentrations of adenosine 5′‐triphosphate (ATP))‐activated photodynamic effect sensitized by long‐wavelength photons is validated for PEG₂₀₀₀‐SiNcTI‐Ph/CpG‐ZIF‐8@CM, advancing the precision of cancer therapy. Moreover, PEG₂₀₀₀‐SiNcTI‐Ph/CpG‐ZIF‐8@CM evades immune surveillance to target CT26 colon tumors in mice mediated by CD47/signal regulatory proteins α (SIRPα) interaction and PD‐1/programmed death ligand 1 (PD‐L1) interaction, respectively. Tumor environment‐activated photodynamic therapy realized by PEG₂₀₀₀‐SiNcTI‐Ph/CpG‐ZIF‐8@CM induces immunogenic cell death (ICD) to elicit anti‐tumor immune response, which is empowered by enhanced dendritic cells (DC) uptake of CpG and PD‐L1 blockade contributed by the nanoplatform. The photodynamic immunotherapy efficiently combats primary and distant CT26 tumors, and additionally generates immune memory to inhibit tumor recurrence and metastasis. The nanoplatform developed here provides insights for the development of precise cancer therapeutic strategies.