Enzyme-Driven Membrane-Targeted Chimeric Peptide for Enhanced Tumor Photodynamic Immunotherapy Chi Zhang Fan Gao Wei Wu Wen-Xiu Qiu Lu Zhang Runqing Li Ze-Nan Zhuang Wuyang Yu Han Cheng Xian-Zheng Zhang 10.1021/acsnano.9b04315.s001 https://acs.figshare.com/articles/journal_contribution/Enzyme-Driven_Membrane-Targeted_Chimeric_Peptide_for_Enhanced_Tumor_Photodynamic_Immunotherapy/9929816 Here, a protein farnesyltransferase (PFTase)-driven plasma membrane (PM)-targeted chimeric peptide, PpIX-C<sub>6</sub>-PEG<sub>8</sub>-KKKKKKSKTKC-OMe (PCPK), was designed for PM-targeted photodynamic therapy (PM-PDT) and enhanced immunotherapy <i>via</i> tumor cell PM damage and fast release of damage-associated molecular patterns (DAMPs). The PM targeting ability of PCPK originates from the cellular K-Ras signaling, which occurs exclusively to drive the corresponding proteins to PM by PFTase. With the conjugation of the photosensitizer protoporphyrin IX (PpIX), PCPK could generate cytotoxic reactive oxygen species to deactivate membrane-associated proteins, initiate lipid peroxidation, and destroy PM with an extremely low concentration (1 μM) under light irradiation. The specific PM damage further induced the fast release of DAMPs (high-mobility group box 1 and ATP), resulting in antitumor immune responses stronger than those of conventional cytoplasm-localized PDT. This immune-stimulating PM-PDT strategy also exhibited the inhibition effect for distant metastatic tumors when combined with programmed cell death receptor 1 blockade therapy. 2019-10-02 15:04:33 PEG 8 inhibition effect cytoplasm-localized PDT Enhanced Tumor Photodynamic Immunotherapy deactivate membrane-associated proteins lipid peroxidation PM damage high-mobility group box 1 PM-targeted photodynamic therapy cell death receptor 1 blockade therapy immune-stimulating PM-PDT strategy photosensitizer protoporphyrin ATP DAMP light irradiation protein farnesyltransferase Enzyme-Driven Membrane-Targeted Chimeric Peptide cytotoxic reactive oxygen species PCPK metastatic tumors PpIX-C 6 tumor cell PM damage