Biomimetic Nano-Cancer Stem Cell Scavenger for Inhibition of Breast Cancer Recurrence and Metastasis after FLASH-Radiotherapy.

ABSTRACT

Compared to conventional radiotherapy (RT), FLASH-RT delivers ultra-high dose radiation, significantly reducing damage to normal tissue while guaranteeing the effect of cancer treatment. However, cancer recurrence and metastasis frequently occur after all RT due to the existence of intractable cancer stem cells (CSCs). To address this, a biomimetic nanoplatform (named TAFL) of tumor-derived exosome fusion liposomes is designed by co-loading aggregation-induced emission photothermal agents, TPE-BBT, and anti-cancer drugs, aspirin, aiming to clear CSCs for inhibiting cancer recurrence and metastasis after FLASH-RT therapy . Aspirin released in TAFL system triggered by laser irradiation can induce apoptosis and DNA damage of 4T1 CSCs, comprehensively downregulate their stemness phenotype, and inhibit their sphericity. Furthermore, the TPE-BBT mediated mild-photothermal therapy can alleviate the hypoxic tumor microenvironment, inhibit the DNA repair of CSCs, which further amplifies the effect of aspirin against CSCs, therefore reduces the effective dose of aspirin, making TAFL more biologically safe. In vivo experimental results demonstrated that decreased CSCs population mediated by TAFL system treatment significantly inhibited tumor recurrence and metastasis after FLASH-RT therapy. In summary, this TAFL system   provides a new idea for the future clinical application of FLASH-RT therapy.