2. Academic Validation
  3. Radiocleavable rare-earth nanoactivators targeting over-expressed folate receptors induce mitochondrial dysfunction and remodel immune suppressive microenvironment in pancreatic cancer

Radiocleavable rare-earth nanoactivators targeting over-expressed folate receptors induce mitochondrial dysfunction and remodel immune suppressive microenvironment in pancreatic cancer

  • J Nanobiotechnology. 2025 Aug 12;23(1):562. doi: 10.1186/s12951-025-03657-8.
Tanvi Gupta 1,  Shang-Rung Wu 2,  Li-Chan Chang 1,  Forn-Chia Lin 3,  Yan-Shen Shan 1 4,  Chen-Sheng Yeh 5 6 7,  Wen-Pin Su 8 9 10 11
Affiliations

Affiliations

  • 1 Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, No. 35, Rd. Xiaodong, Tainan, 704, Taiwan.
  • 2 School of Dentistry & Institute of Oral Medicine, College of Medicine, National Cheng Kung University, Tainan City, 701, Taiwan.
  • 3 Department of Radiation Oncology, College of Medicine, National Cheng Kung University Hospital, National Cheng Kung University, Tainan, 704, Taiwan.
  • 4 Department of Surgery, College of Medicine, National Cheng Kung University Hospital, National Cheng Kung University, Tainan, 704, Taiwan.
  • 5 Department of Chemistry, National Cheng Kung University, Tainan, 701, Taiwan.
  • 6 Center of Applied Nanomedicine, National Cheng Kung University, Tainan, 704, Taiwan.
  • 7 Department of Medicinal and Applied Chemistry, Kaohsiung Medical University, Kaohsiung, 807, Taiwan.
  • 8 Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, No. 35, Rd. Xiaodong, Tainan, 704, Taiwan. wpsu@mail.ncku.edu.tw.
  • 9 Center of Applied Nanomedicine, National Cheng Kung University, Tainan, 704, Taiwan. wpsu@mail.ncku.edu.tw.
  • 10 Departments of Oncology and Internal Medicine, College of Medicine, National Cheng Kung University Hospital, National Cheng Kung University, Tainan, 704, Taiwan. wpsu@mail.ncku.edu.tw.
  • 11 Clinical Medicine Research Center, College of Medicine, National Cheng Kung University Hospital, National Cheng Kung University, Tainan, 704, Taiwan. wpsu@mail.ncku.edu.tw.
PMID: 40797208 DOI: 10.1186/s12951-025-03657-8
Abstract

Pancreatic Cancer is a fatal Cancer with poor prognosis and survival rate, often diagnosed usually in the advanced stage of disease. The conventional methods are usually considered for surgery or chemotherapy, and neo-adjuvant therapies have improved the survival rate in the patients. Folic acid plays a crucial role in the synthesis, metabolism, and repair of DNA; thereby, it is considered one of the biomolecules for cancer-targeted therapy for highly expressed receptors to overcome poor vasculature and dense tumor stroma, as in pancreatic Cancer. This study strategizes for improving the therapeutic efficacy of pancreatic Cancer via folate receptor-guided nanoparticles. The conjugation of folic acid (FA) to the LiYF4:Ce3+nanoparticles (SCNP-FA) with the photocleavage chemical molecule; firstly enters the cells through receptor-mediated endocytosis and then, releases FA intracellularly upon the trigger of radiation in a controlled manner. This nano-based approach induces Ferroptosis to provoke immunogenic cell death (ICD) with higher generation of Reactive Oxygen Species (ROS) and accumulation of lipid peroxides. It shows an abundant damage to the mitochondria and a decrease in mitochondrial membrane potential (MMP) upon treatment. This targeted therapy remodels the immunosuppressive tumor microenvironment and releases damage-associated molecular patterns (DAMPs) to initiate an immune response. These findings reveal the anti-tumor response with folate receptor-guided nanoparticles in pancreatic Cancer.

Keywords

Ferroptosis; Folate receptor; Folic acid; Immunogenic cell death; Nano therapy.

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