Light-triggered photosynthetic engineered bacteria for enhanced-photodynamic therapy by relieving tumor hypoxic microenvironment

Background: Singlet oxygen (¹O₂) has received considerable research attention in photodynamic therapy (PDT) due to its cytotoxic solid features. However, the inherent hypoxic state of the tumor microenvironment (TME) leads to the meager ¹O₂ quantum yield of inorganic PDT reagents, and their application in vivo remains elusive. Methods: We developed a novel strategy to fabricate active photosynthetic bacteria/photosensitizer/photothermal agent hybrids for photosynthetic tumor oxygenation and PDT and PTT tumor therapy under different laser irradiation sources. Photosynthetic bacteria combined with Ce6 photosensitizer and Au NPs photothermal agent, the obtained Bac@Au-Ce6 effectively targets tumor tissues and further enhances the tumor accumulation of Au-Ce6. Results: The results showed that the Au-Ce6-loaded engineered bacteria (Bac@Au-Ce6) maintained the photosynthetic properties of Syne. After i.v. injection, Bac@Au-Ce6 efficiently aggregates at tumor sites due to the tumor-targeting ability of active Syne. With 660 nm laser irradiation at the tumor site, the photoautotrophic Syne undergoes sustained photosynthetic O₂ release and immediately activates O₂ to ¹O₂ via a loaded photosensitizer. PTT was subsequently imparted by 808 laser irradiations to enhance tumor killing further. Conclusions: This work provides a new platform for engineering bacteria-mediated photosynthesis to promote PDT combined with PTT multi-faceted anti-tumor.