2. Academic Validation
  3. Intranasal delivery of AEP inhibitor-loaded neuron-targeted liposome ameliorates radiation-induced brain injury

Intranasal delivery of AEP inhibitor-loaded neuron-targeted liposome ameliorates radiation-induced brain injury

  • Mater Today Bio. 2025 Feb 11:31:101568. doi: 10.1016/j.mtbio.2025.101568.
Keman Liao 1 2 3,  Yan Gao 4 5,  Mengdan Cheng 4 5,  Yibing Zhang 1 2 3,  Jianyi Zhao 1 2 3,  Li Zhou 1 2 3,  Ran Wu 1 2 3,  Gang Cai 1 2 3,  Lu Cao 1 2 3,  Jiayi Chen 1 2 3,  Yingying Lin 1 2 3
Affiliations

Affiliations

  • 1 Department of Radiation Oncology, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, 200025, China.
  • 2 Shanghai Key Laboratory of Proton-Therapy, Shanghai, 201801, China.
  • 3 Institute for Medical Imaging Technology, Shanghai, 201800, China.
  • 4 Department of Neurosurgery, Jiangnan University Medical Center, 214000, China.
  • 5 Wuxi neurosurgical Institute, Jiangsu, 214000, China.
PMID: 40026629 DOI: 10.1016/j.mtbio.2025.101568
Abstract

Acute exposure to high-dose radiation during head and neck tumors radiotherapy can result in radiation-induced brain injury (RIBI), characterized by neurocognitive deficits, dementia, and epilepsy. Asparagine endopeptidase (AEP), a cysteine proteinase, is effective in preventing neurodegenerative diseases and RIBI. However, the limited permeability of selective AEP inhibitor (AEPI) delivery to the brain reduces its effectiveness in preventing RIBI. This study constructed a nose-to-brain delivery platform for AEPI by encapsulating it in liposomes that are surface modified with rabies virus glycoprotein (RVG29), creating RVG29-AEPI liposomes. These RVG29-AEPI liposomes demonstrated efficient cellular uptake and blood-brain barrier penetration in vitro and in vivo. RVG29-AEPI liposomes effectively shielded DNA from radiation-induced damage and resulted in more effective Reactive Oxygen Species removal than liposomes in primary neurons and microglial cells. Notably, the treatment with RVG29-AEPI liposomes (10 mg/kg AEPI) was highly systemically safe and significantly reduced brain injury. Behavioral tests demonstrated that RVG29-AEPI liposomes-treated mice had less radiation-induced brain damage and motor dysfunction. Moreover, it significantly prevented neuronal injury and microglia cell activation under photon and modern proton irradiation. These findings demonstrate the potential of nose-to-brain medication delivery of RVG29-AEPI liposomes for effective radioprotection, indicating a viable technique with enormous potential for clinical translation.

Keywords

Asparagine endopeptidase; Liposomes; Nose-to-brain; Radiation-induced brain injury.

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