Magnetically guided transferrin-modified liposomes boost brain delivery of harmine for glioblastoma therapy
Innovative liposomal system targets glioma cells, enhances drug accumulation, and reduces neurotoxicity.
image: Schematic illustration of the synthesis of HM@MNLs-Tf—magnetic nanoliposomes loaded with the anti-tumor compound harmine and surface-modified with transferrin for glioblastoma targeting—and their proposed anti-glioma mechanism. The formulation combines transferrin receptor-mediated transport across the blood–brain barrier with external magnetic guidance, enabling precise accumulation in glioblastoma cells, sustained drug release in the acidic tumor microenvironment, and reduced neurotoxicity by limiting harmine exposure to healthy brain tissue.
Credit: Xiaohui Tang et al., [Nano research, 2025]
Magnetically Guided, Transferrin-Modified Nanoliposomes Boost Precision Delivery of Harmine for Glioblastoma Treatment While Reducing Neurotoxicity
Glioblastoma – the most aggressive and common type of brain cancer – has long challenged clinicians due to its rapid growth, invasive nature, and the inability of most drugs to cross the brain’s protective blood–brain barrier (BBB). Now, a team of Chinese researchers has developed a dual-targeted nanoliposome system that uses both magnetic guidance and receptor-specific targeting to deliver the plant-derived anti-tumor compound harmine (HM) directly to brain tumors, significantly enhancing treatment efficacy while reducing toxic side effects on the central nervous system.
This work, led by Huige Zhou (National Center for Nanoscience and Technology, CAS), Xiaohui Tang and Mei Wang (Xinjiang Medical University) integrates cutting-edge nanotechnology with established biological targeting principles. Their study reports the creation of magnetic nanoliposomes—lipid-based nanoparticles embedded with iron oxide nanoparticles—further modified on the surface with the brain tumor–targeting ligand transferrin (Tf). This specially engineered formulation, termed HM@MNLs-Tf, simultaneously exploits the over expression of transferrin receptors on glioblastoma cells and brain endothelial cells, and employs an externally applied magnetic field to physically help the particles across the BBB to the tumor site.
“Harmine is a promising anti-glioblastoma agent extracted from Peganum harmala seeds, but its poor solubility, low bioavailability, and neurotoxic side effects have so far limited its therapeutic use,” explained Mei Wang, corresponding author of the paper. “Our goal was to increase its tumor selectivity and brain delivery efficiency, while mitigating harmine’s tendency to affect normal brain tissue.”
Double Targeting: Magnetic Guidance plus Transferrin Receptor Binding
In HM@MNLs-Tf, citric-acid–coated iron oxide nanoparticles (Fe₃O₄@CA) act as the magnetic core. When an external magnetic field is applied over the tumor region, the particles are attracted across the BBB and retained at the tumor site. The transferrin ligands on the liposome surface further triggered receptor-mediated endocytosis in glioblastoma cells, ensuring that more drug-carrying nanoparticles are internalized by cancer cells rather than healthy neurons or glia.
Laboratory experiments showed that the optimally formulated HM@MNLs-Tf nanoparticles had an average size of ~200 nm, high encapsulation efficiency (>68%), and sustained drug release, especially in the acidic tumor microenvironment. They also demonstrated excellent stability over two weeks of storage.
Enhanced BBB Penetration and Tumor Uptake
In vitro BBB models using mouse brain microvascular endothelial cells confirmed that Tf modification doubled nanoparticle permeability compared to unmodified nanoliposomes, while the combination of Tf and magnetic targeting improved permeability more than threefold. In live mice, fluorescence and MRI imaging confirmed that HM@MNLs-Tf accumulated in the brain more efficiently and for longer periods under magnetic guidance.
“This dual-target strategy effectively addresses two of the biggest challenges in glioblastoma chemotherapy: penetrating the BBB and ensuring drug accumulation in the tumor rather than normal tissue,” said Huige Zhou.
Tumor Suppression with Reduced Neurotoxicity
In glioblastoma-bearing mice, HM@MNLs-Tf combined with magnetic targeting significantly inhibited tumor growth compared to free harmine or non-targeted formulations. Tumor weight and volume were markedly reduced, and histological analysis showed increased tumor cell apoptosis, reduced proliferation, and minimal damage to healthy organs.
Importantly, HM@MNLs-Tf also alleviated harmine’s well-documented CNS side effects. Free harmine, which readily crosses into normal brain tissue, can cause tremors, hypothermia, and disturbances in serotonin (5-HT) metabolism due to inhibition of monoamine oxidase A (MAO-A). In contrast, mice treated with HM@MNLs-Tf under magnetic targeting had lower tremor scores, milder temperature drops, and largely preserved normal neurotransmitter levels.
“Our delivery system reduced the extent and duration of MAO-A inhibition in the brain, which in turn minimized serotonin spikes and downstream neurotoxic effects,” said Ru Bai. “This makes harmine a much safer candidate for potential clinical application in glioblastoma therapy.”
Potential Beyond Harmine
The researchers emphasize that the magnetically guided transferrin-modified liposome system could be adapted for other drugs that suffer from poor BBB permeability or systemic toxicity. “This platform not only improves harmine therapy, but also provides a versatile carrier for delivering diverse anticancer agents or CNS-targeting therapeutics,” noted Xiaohui Tang, the first author of this work.
The study was supported by the Beijing Natural Science Foundation, the National Natural Science Foundation of China, the Beijing Nova Program, the CAMS Innovation Fund for Medical Sciences, and other grants.
Other contributors include Shihui Liu, Rongrong Qiao, Tao Liu and Jiakun Zhang from the New Cornerstone Science Laboratory, CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology, Beijing, China; and the University of Chinese Academy of Sciences, Beijing, China; as well as Chunying Chen from the New Cornerstone Science Laboratory and University of Chinese Academy of Sciences; all working in collaboration with the Research Unit of Nanoscience and Technology, Chinese Academy of Medical Sciences, Beijing, China.
This work was supported by the Beijing Natural Science Foundation (7252296, 7242268), National Natural Science Foundation (82460366, 81460539), Beijing Nova Program (20250484935), CAMS Innovation Fund for Medical Sciences (CIFMS 2019-I2M-5-018), HAAFS Agriculture Science and Technology Innovation Project (2022KJCXZX-SSS-7).
About Nano Research
Nano Research is a peer-reviewed, open access, international and interdisciplinary research journal, sponsored by Tsinghua University and the Chinese Chemical Society, published by Tsinghua University Press on the platform SciOpen. It publishes original high-quality research and significant review articles on all aspects of nanoscience and nanotechnology, ranging from basic aspects of the science of nanoscale materials to practical applications of such materials. After 18 years of development, it has become one of the most influential academic journals in the nano field. Nano Research has published more than 1,000 papers every year from 2022, with its cumulative count surpassing 7,000 articles. In 2024 InCites Journal Citation Reports, its 2024 IF is 9.0 (8.7, 5 years), and it continues to be the Q1 area among the four subject classifications. Nano Research Award, established by Nano Research together with TUP and Springer Nature in 2013, and Nano Research Young Innovators (NR45) Awards, established by Nano Research in 2018, have become international academic awards with global influence.