780-ProNP@rsl3 induces ferroptosis via lung-to-tumor progressive-targeting and enhances tumor immune infiltration in lung cancer

Ferroptosis is an iron-dependent programmed cell death functioned by divalent iron ions inducing lipid peroxidation to cause cell death. However, therapeutic efficacy relies on successful targeted delivery into tumor cells, where nanovehicles face the predicament of efficiently traversing endothelia and attaching to tumor cells. According to published literature and our previous studies, nanoparticles containing IR780 iodide—the well-known tumor-targeting fluorescent molecule—sometimes exhibited superior lung-specific accumulation, and free IR780 iodide indeed can specifically target the lung, which indicated its adoption to achieve the organ-to-lesion targeted anti-cancer therapy to treat lung carcinoma. This study aimed to investigate the mechanism of IR780 iodide targeting to the lung and employed a lung-to-tumor progressive-targeting strategy to perform RSL3-induced ferroptosis for treating lung cancer. The loading of IR780 on the surface of the nanovehicles achieved the exposure of its chemical structure, which revealed the lung-specific accumulation characteristic of 780-ProNP@rsl3. In vivo fluorescent imaging and LSCM observation showed that 780-ProNP@rsl3 exhibited potent lung-targeting ability in an infiltrating manner, with low off-target accumulation in the liver and spleen. 780-ProNP@rsl3 was further proved to show high lung-to-tumor-targeting efficiency, which facilitated the subsequent tumor cell internalization after nanoparticles traversed the pulmonary endothelial cell barrier. 780-ProNP@rsl3 exhibited potent capacity in inducing the accumulation of Fe2+, ROS and lipid peroxidation in vitro, inflamed tumor immune microenvironment, and inhibited tumor progression. By progressively targeting pulmonary endothelia and tumors deep inside, 780-ProNP@rsl3 conquered the low intratumoral delivery efficiency caused by pulmonary endothelial entrapment and exhibited highly efficient intratumor release of RSL3, which orchestrated the tumor immune microenvironment into an inflamed status and induced ferroptosis with decreased influence in normal lung tissues, leading to the suppression of lung cancer progression. Such a progressively targeting strategy provided a prospective choice for treating lung tumors.