Armed Macrophages as Hunters for Photodynamic Therapy of Systemic Bacterial Infections by Bathing in the Sunshine

There has been a vision to conduct therapy using sunlight since ancient Greece, Egypt, and India. In modern medicine, photodynamic therapy is one popular form of therapy that uses light to excite photosensitizers to eliminate malignant and other diseased cells. It offers highly effective and broad-spectrum therapeutic efficacy. Yet, there are several hindrances to a real treatment of disease through photodynamic therapy, such as the limitation on the irradiation depth and areas, the regulation of side effects, etc. Usually, the patients should be kept in a dark environment during and after the therapeutic process for days to avoid side effects induced by light in daily life, not mention to conduct the phototherapy through sunbathing. Based on the above consideration, we propose an innovative idea to bring photodynamic therapy back to the origin of phototherapy-bathing in the sunshine. Namely, we designed a "live drug", as a smart hunter, named A-RAWs, by loading an "off-on" type of photosensitizer in macrophages to solve two technical problems. Firstly, to find and capture bacteria accurately, and then transport these bacteria to the epidermis through the blood capillary, where sunlight is reachable. Secondly, to minimize the potential side effects and maximize the therapeutic time windows and efficacy by using bacteria as the trigger of the photodynamic effect. Specifically, we first designed and synthesized a lysosome-targeted and inflammation-activated NIR photosensitizer (Lyso710A), and loaded it in the lysosomes of macrophages. These "armed" macrophages were transferred into the infected host to capture deep-tissue bacteria through innate immunity and transport the captured bacteria through the bloodstream to superficial skin. Finally, the pathogenic bacteria are killed by the photodynamic effect when transported to the epidermis and receive sunbathing. In vivo experiment demonstrates a 100% therapeutic efficiency on systemic bacterial infection model. We also demonstrated the working mechanism of this "live drug" using a lung infection model. This hunter demonstrates high intelligence to break the limitations of current photodynamic therapy and executes photodynamic therapy of deep-tissue bacterial infection simply by bathing in the sunshine. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=182 SRC="FIGDIR/small/574019v1_ufig1.gif" ALT="Figure 1"> View larger version (92K): org.highwire.dtl.DTLVardef@11331aeorg.highwire.dtl.DTLVardef@122baf6org.highwire.dtl.DTLVardef@1208bd5org.highwire.dtl.DTLVardef@1bc672c_HPS_FORMAT_FIGEXP M_FIG C_FIG