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

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

  • Biomaterials. 2026 Jul:330:124002. doi: 10.1016/j.biomaterials.2026.124002.
Seungyong Shin 1,  Ga-Hyun Bae 2,  Joo Dong Park 1,  Eun-Young Koh 2,  Seunghyo Ko 1,  Jieun Han 3,  Chun Gwon Park 4,  Dong-Hyun Kim 5,  Kun Na 6,  Wooram Park 7
Affiliations

Affiliations

  • 1 Department of Integrative Biotechnology, College of Biotechnology and Bioengineering, Sungkyunkwan University (SKKU), Seobu-ro 2066, Suwon, Gyeonggi, 16419, Republic of Korea.
  • 2 Department of MetaBioHealth, Institute for Cross-disciplinary Studies (ICS), SKKU, Seobu-ro 2066, Suwon, Gyeonggi, 16419, Republic of Korea.
  • 3 Department of Integrative Biotechnology, College of Biotechnology and Bioengineering, Sungkyunkwan University (SKKU), Seobu-ro 2066, Suwon, Gyeonggi, 16419, Republic of Korea; Institute of Biotechnology and Bioengineering, College of Biotechnology and Bioengineering, SKKU, Seobu-ro 2066, Suwon, Gyeonggi, 16419, Republic of Korea.
  • 4 Department of Biomedical Engineering, ICS, SKKU, Seobu-ro 2066, Suwon, Gyeonggi, 16419, Republic of Korea.
  • 5 Department of Radiology, Feinberg School of Medicine, Northwestern University, Chicago, IL, 60611, USA; Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, IL, 60611, USA; Department of Biomedical Engineering, McCormick School of Engineering, Northwestern University, Evanston, IL, 60208, USA; Department of Biomedical Engineering, University of Illinois, Chicago, IL, 60607, USA.
  • 6 Department of Biomedical-Chemical Engineering, The Catholic University of Korea, Jibong-ro 43, Bucheon, Gyeonggi, 14662, Republic of Korea; Department of Biotechnology, The Catholic University of Korea, Jibong-ro 43, Bucheon, Gyeonggi, 14662, Republic of Korea.
  • 7 Department of Integrative Biotechnology, College of Biotechnology and Bioengineering, Sungkyunkwan University (SKKU), Seobu-ro 2066, Suwon, Gyeonggi, 16419, Republic of Korea; Department of MetaBioHealth, Institute for Cross-disciplinary Studies (ICS), SKKU, Seobu-ro 2066, Suwon, Gyeonggi, 16419, Republic of Korea; Institute of Biotechnology and Bioengineering, College of Biotechnology and Bioengineering, SKKU, Seobu-ro 2066, Suwon, Gyeonggi, 16419, Republic of Korea. Electronic address: [email protected].
PMID: 41570670 DOI: 10.1016/j.biomaterials.2026.124002
Abstract

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.

Keywords

7-Dehydrocholesterol; Ferroptosis; Immunogenic cell death; Lipid nanoparticles; Radiosensitizer; Radiotherapy.

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