Transforming lipid nanoparticles into radio-activatable therapeutics through synergistic ferroptosis for enhanced cancer radiotherapy.

Radiotherapy (RT) is a cornerstone of cancer treatment, but its efficacy is often compromised by robust antioxidant defense mechanisms that counteract radiation-induced oxidative stress. In this study, we developed a novel dual-action nanoplatform, termed radio-activatable lipid nanoparticles (RaLNPs), designed to enhance radiosensitivity by amplifying radiation-induced ferroptosis. RaLNPs incorporate both siRNA targeting glutathione peroxidase 4 (siGPX4), a key ferroptosis defense antioxidant enzyme, and 7-dehydrocholesterol (7-DHC), a radiation-reactive lipid. Notably, the structural lipid cholesterol was completely replaced with 7-DHC, thereby designing the carrier itself to possess a therapeutic function activated by irradiation. The engineered RaLNPs exerted a dual-action mechanism by suppressing GPX4 expression to disable the ferroptosis defense system and, upon irradiation, amplifying 7-DHC-mediated radical chain reactions. Importantly, RaLNPs did not induce oxidative stress or ferroptosis in the absence of radiation, whereas therapeutic irradiation selectively triggered potent and iron-dependent ferroptosis. Beyond direct tumor cell killing, this ferroptotic process also elicited the key hallmarks of immunogenic cell death (ICD), thereby promoting dendritic cell maturation. In a syngeneic 4T1 breast cancer mouse model, the combination of RaLNPs and a single dose of radiation exhibited superior suppression of primary tumor growth and was accompanied by a reduction in metastatic lesions, without systemic toxicity. Analysis of tumor tissues revealed that this therapeutic efficacy was driven by a coordinated immune response, linking T-cell priming in tumor-draining lymph nodes to the sustained intratumoral infiltration of functional cytotoxic T lymphocytes. In conclusion, the RaLNPs developed in this study act as innovative radio-activatable radiosensitizers that simultaneously induce tumor cell death and antitumor immunity specifically in response to irradiation. This work highlights a transformative strategy in which a conventional lipid nanoparticle carrier is evolved into an active therapeutic to overcome the limitations of radiotherapy.