Radiation-triggerable bioreactors enable bioenergetic reprograming of cancer stem cell plasticity via targeted arginine metabolism disruption for augmented radio-immunotherapy

Cancer stem cells (CSCs) are a major cause for the insufficient tumor eradication in the clinic, which universally present enhanced mitochondrial oxidative phosphorylation (OXPHOS) to facilitate stemness maintenance and drive treatment resistance. Herein, we report a nanointegrative radiation-triggerable bioreactor (RTB) that selectively remodels CSC-intrinsic arginine metabolism to bioenergetically reprogram CSCs towards a therapeutically-vulnerable differentiated state, leading to durable radio-immunotherapeutic responses in vivo. The RTB nanosystem was developed through the supramolecular integration of radioresponsive iNOS-expressing genetic circuits (pDNA^iNOS) and β-lapachone (LAP) into CSC-targeting cationic liposomes. Low-dose radiotherapy (LDR)-induced Nrf2 upregulation readily activates pDNA^iNOS to express excessive iNOS, which then depletes CSC-intrinsic arginine while generating abundant nitric oxide (NO) for in-situ amplification of LDR-mediated cytotoxicity. Meanwhile, LDR also upregulates NQO1 expression to promote LAP-mediated ROS generation. These effects could act in a cooperative manner to potently damage CSC mitochondria, which not only blocks OXPHOS activity to drive the differentiation of CSCs for abolishing their self-renewal and resistance capability, but also enhances their propensity towards immunogenic necroptosis to elicit adaptive antitumor immunity, showing significant potential for treating therapy-persistent tumors.