Complementing Cancer Photodynamic Therapy with Ferroptosis through Iron Oxide Loaded Porphyrin-Grafted Lipid Nanoparticles.

Nanomaterials that combine multimodality imaging and therapeutic functions within a single nanoplatform have drawn extensive attention for molecular medicines and biological applications. Herein, we report a theranostic nanoplatform based on a relatively smaller (<20 nm) iron oxide loaded porphyrin-grafted lipid nanoparticles (FeO@PGL NPs). The amphiphilic PGL easily self-assembled on the hydrophobic exterior surface of ultrasmall FeO NPs, resulting in a final ultrasmall FeO@PGL NPs with diameter of ∼10 nm. The excellent self-assembling nature of the as-synthesized PGL NPs facilitated a higher loading of porphyrins, showed a negligible dark toxicity, and demonstrated an excellent photodynamic effect against HT-29 cancer cells . The experimental results further confirmed that FeO@PGL NPs were ideally qualified for both the fluorescence and magnetic resonance (MR) imaging guided nanoplatforms to track the biodistribution and therapeutic responses of NPs as well as to simultaneously trigger the generation of highly cytotoxic reactive oxygen species (ROS) necessary for excellent photodynamic therapy (PDT). After recording convincing therapeutic responses, we further evaluated the ability of FeO@PGL NPs/FeO@Lipid NPs for ferroptosis therapy (FT) via tumor microenvironment (TME) modulation for improved anticancer activity. We hypothesized that tumor-associated macrophages (TAMs) could significantly improve the efficacy of FT by accelerating the Fenton reaction . In our results, the Fe ions released directly contributed to the Fenton reaction, whereas the presence of RAW 264.7 macrophages further accelerated the ROS generation as observed by the fluorescence imaging. The significant increase in the ROS during the coincubation of NPs, endocytosed by HT-29 cells and RAW264.7 cells, further induced increased cellular toxicity of cancer cells.