Conventional photodynamic therapy (PDT) approaches face challenges including limited light penetration, low uptake of photosensitizers by tumors, and lack of oxygen in tumor microenvironments. One promising solution is to internally generate light, photosensitizers, and oxygen. This can be accomplished through endogenous production, such as using bioluminescence as an endogenous light source, synthesizing genetically encodable photosensitizers in situ, and modifying cells genetically to express catalase enzymes. Furthermore, these strategies have been reinforced by the recent rapid advancements in synthetic biology. In this review, we summarize and discuss the approaches to overcome PDT obstacles by means of endogenous production of excitation light, photosensitizers, and oxygen. We envision that as synthetic biology advances, genetically engineered cells could act as precise and targeted “living factories” to produce PDT components, leading to enhanced performance of PDT.

Significance: Silent biosynthetic gene clusters represent fertile grounds for the discovery of new small molecules, and a number of approaches have been developed for activating them. Their regulation, however, has received far less attention, especially in Gram-negative bacteria. Here, we show that a LysR-type transcriptional regulator, which we name scmR , acts as a gatekeeper of secondary metabolism and virulence in the model organism Burkholderia thailandensis E264. Specifically, genetic, chemical, and “omics”-based approaches unveil ScmR as a master regulator that interacts with pathway-specific transcriptional regulators to control, and primarily suppress, secondary metabolism. Because this gene is conserved in other Burkholderia species, our results suggest that scmR -mediated control of secondary metabolism and virulence may be common within this genus and the Pseudomallei -group pathogens.