Upconversion nanoparticle-based optogenetic nanosystem for photodynamic therapy and cascade gene therapy

Most photosensitizer molecules used for the photodynamic therapy (PDT) are chemically-synthesized or-ganic photosensitizer dyes which show several limitations such as unsatisfactory cell uptake, weak selec-tivity and off-target phototoxicity. Recently, genetically-encoded photosensitizers have attracted increas-ing attentions which provide the targeted cell elimination with single-cell precision. However, their ap-plications are mainly limited by the shallow tissue penetration depth of the excitation light and the low cell apoptosis ratio. Herein, we developed a feasible upconversion nanoparticle (UCNP)-based optoge-netic nanosystem with three-in-one functional integration: bio-imaging, NIR-triggered PDT and cascade gene therapy. Firstly, the mitochondria-targeted genetically-encoded photosensitizer was constructed and transfected into cancer cells. Then, the functional upconversion nanoprobe was constructed with the mi-tochondria targetability and then the siRNA was loaded on the surface of UCNPs via the reactive oxygen species (ROSs) sensitive chemical bond. After the transfection and incubation, both of the upconversion nanoprobe and the genetically-encoded photosensitizer were accumulated in the mitochondria of cancer cells. Under the NIR irradiation, the emission of UCNPs could excite the expressed protein photosensi-tizer to generate ROSs which then stimulated the release of siRNAs in a controllable manner, achieving PDT and cascade gene therapy. Since the generation of ROSs and the release of siRNA occurred in the mitochondria in-situ , the mitochondria-mediated cell apoptosis signal pathway would be activated to in-duce cell apoptosis and subsequently inhibit tumor growth. To the best of our knowledge, this is the first report about NIR laser-activated, organelle-localized genetically-encoded photosensitizers developed for cascade therapy, which will widen the application of optogenetic tools in the tumor therapy.The application of genetically-encoded photosensitizers in photodynamic therapy (PDT) is mainly lim-ited by the shallow tissue penetration depth of the excitation light and unsatisfactory therapeutic perfor-mance. In this experiment, we developed an upconversion nanoparticles-based optogenetic nanosystem to enhance the PDT and cascade gene therapy for malignant tumors. The expressed genetically-encoded photosensitizers were accumulated in the mitochondria, which were activated in situ by the upconversion nanoprobe. Besides, the photogenerated reactive oxygen species (ROSs) stimulated the release of siRNAs in a controllable manner. To the best of our knowledge, this is the first report about NIR laser-activated, genetically-encoded photosensitizers developed for organelle-localized controllable cascade therapy. We hope this work can accelerate the application of genetically-encoded photosensitizers in the tumor ther-apy.(c) 2022 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.

Automated summary

Researchers developed an upconversion nanoparticle-based optogenetic nanosystem for enhanced photodynamic therapy and cascade gene therapy. Genetically-encoded photosensitizers were localized in mitochondria and activated by upconversion nanoprobe to generate reactive oxygen species, controlling the release of siRNA and inducing cancer cell apoptosis.