2. Academic Validation
  3. Ion-interference amplifier nano-system enhances radiotherapy via mitochondrial dysfunction and efferocytosis Inhibition

Ion-interference amplifier nano-system enhances radiotherapy via mitochondrial dysfunction and efferocytosis Inhibition

  • J Nanobiotechnology. 2025 Nov 25;23(1):737. doi: 10.1186/s12951-025-03808-x.
Shuting Zheng # 1 2,  Yinfei Zheng # 1 2,  Honglei Hu # 1 3,  Minyi Liu 2,  Chenxi He 1 2,  Zede Wu 1 2,  Meirong Hou 1 2,  Guoqiang Liu 4,  Yikai Xu 5,  Chenggong Yan 6 7,  Bingxia Zhao 8 9
Affiliations

Affiliations

  • 1 Department of Medical Imaging Center, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China.
  • 2 Cancer Research Institute, School of Basic Medical Sciences, Southern Medical University, Guangzhou, 510515, China.
  • 3 The Radiology Department, The Second Affiliated Hospital, Guangzhou Medical University, Guangzhou, 510260, China.
  • 4 Institute of Electrical Engineering, Chinese Academy of Sciences, Beijing, 100190, China.
  • 5 Department of Medical Imaging Center, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China. [email protected].
  • 6 Department of Medical Imaging Center, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China. [email protected].
  • 7 Guangdong Provincial Key Laboratory of Cardiac Function and Microcirculation, Guangzhou, 510515, China. [email protected].
  • 8 Cancer Research Institute, School of Basic Medical Sciences, Southern Medical University, Guangzhou, 510515, China. [email protected].
  • 9 Experiment Education/Administration Center, School of Basic Medical Sciences, Southern Medical University, Guangzhou, 510515, China. [email protected].
  • # Contributed equally.
PMID: 41291692 DOI: 10.1186/s12951-025-03808-x
Abstract

Background: The efficacy of radiotherapy (RT) is often compromised by tumor radioresistance and an immunosuppressive microenvironment. Two key limitations are the clearance of apoptotic cells (efferocytosis), which can promote an immunosuppressive phenotype, and the acidic tumor microenvironment (TME) that further restrains antitumor immunity. An ideal radiosensitizer should not only enhance radiation-induced cell death but also address these immunological barriers to unlock robust systemic antitumor immunity.

Methods: We constructed a multifunctional nano-system based on mesoporous organosilicon (HMON) as a template. Leveraging the tunability of the -Si-O-Si- framework, we incorporated manganese (Mn) and calcium (CA) elements to form a unique -Si-O-M- hybrid structure (M = Mn or CA). This composite was subsequently loaded with Omeprazole sodium (PPI) and efferocytosis inhibitor, and the surface was modified with hyaluronic acid (HA) for active targeting. In vitro, the radiosensitizing mechanism was investigated in 4T1 cells via western blot, immunofluorescence and flow cytometry. In vivo efficacy was evaluated in 4T1 tumor-bearing BALB/c mice following combined nano-system and RT treatment.

Results: The resulting nano-system exhibited a high T1 relaxivity (r1 = 8.95 mM⁻¹s⁻¹). In vitro and in vivo studies demonstrated that it significantly enhanced radiation-induced oxidative stress and mitochondrial dysfunction. The combination therapy achieved a remarkable ~ 96% tumor growth inhibition in 4T1 tumor-bearing mice. Crucially, it potentiated immunogenic cell death and activated the cGAS-STING pathway, evidenced by a > 3-fold increase in mature dendritic cells (DCs) and a > 4-fold enhancement in tumor-infiltrating cytotoxic T lymphocytes.

Conclusion: This study presents a novel "ion-interference amplifier" strategy that concurrently enhances radiosensitization and immune response, offering a powerful model for synergistic radio-immunotherapy. Meanwhile, the integration of MRI-based tracking further underscores its potential for clinical translation.

Keywords

Efferocytosis inhibition; Molecular imaging; Radiosensitization; Tumor microenvironment; pH regulation.

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