Engineered cyanobacteria-FeO hybrid system as oxygen generator and photosensitizer production factory for synergistic cancer PDT-immunotherapy.

The combination of photodynamic therapy (PDT)-immunotherapy has brought much hope for cancer patients. However, the hypoxia tumor microenvironment (TME) can regulate tumor angiogenesis and inhibit immune response, thus limiting the therapeutic effects. In this paper, engineered cyanobacteria-M2-like tumor-associated macrophages (TAMs) targeting peptide modified FeO nanoparticles hybrid system (ECyano@FeO-M2pep) was constructed for alleviating hypoxia and relieving immune suppression to achieve synergistic cancer PDT-immunotherapy. With the irradiation of red laser, oxygen was produced by the photosynthesis of ECyano to alleviate the hypoxia TME. Then, ECyano could secret 5-aminolevulinic acid (5-ALA) under the induction of theophylline for controllable PDT. In the process of PDT, the disulfide bond between ECyano and FeO-M2pep was broken in response to reactive oxygen species (ROS), and then FeO-M2pep was released to target M2-like TAMs, corresponding by the polarization of M2-like TAMs to M1-like TAMs for the killing of tumor cells. Compared with other groups, ECyano@FeO-M2pep + theophylline + laser (ECyano@FeO-M2pep + T + L) group displayed the lowest tumor volume (159.3 mm) and the highest M1/M2 ratio (1.25- fold). We believe that this hybrid system will offer a promising way for the biomedical application of bacterial therapy.