Mitochondria-targeted nanospheres with deep tumor penetration for photo/starvation therapy

Tumor masses are three-dimensional (3D). The abnormal physiology of solid tumors is a great barrier to anticancer drug delivery, and the development of effective therapeutic strategies for cancer treatment remains highly challenging. In this study, we have rationally designed IR780 and glucose oxidase (GOx) based poly lactic-co-glycolic acid (PLGA) nanospheres, which can not only selectively accumulate in mitochondria, but also penetrate into 3D tumors deeply at the same time, achieving synergistic treatment of phototherapy and enzyme (GOx)-induced starvation therapy under dual-imaging guidance/monitoring. The lipophilic cationic properties of IR780 enable the nanospheres to penetrate into deep tumor tissues, which has been demonstrated byin vitro3D tumor modeling andin vivotumor reconstruction. Meanwhile, the inherent structure of IR780 endows the nanospheres with mitochondrial targeting capability. As mitochondria are susceptible to hyperpyrexia and reactive oxygen species (ROS), mitochondria-targeted phototherapy shows more efficient therapeutic performance. Furthermore, the starvation effect of GOx can cut off the nutrition supply to tumor cells, enhancing the energy metabolism disorder of tumor cells after mitochondrial damage induced by phototherapy, further increasing the damage to tumor cells. In addition, the therapeutic process can be guided/monitored by photoacoustic (PA) and fluorescence (FL) dual imaging. Due to the incorporation of multiple modalities, these nanospheres are promising for cancer theranostics.