Theranostics 2020; 10(14):6122-6135. doi:10.7150/thno.42234

Research Paper

BBB-penetrating codelivery liposomes treat brain metastasis of non-small cell lung cancer with EGFRT790M mutation

Weimin Yin1,2,#, Yuge Zhao1,3,#, Xuejia Kang1, Pengfei Zhao1, Xuhong Fu1, Xiaopeng Mo1, Yakun Wan1, Yongzhuo Huang1,4,✉

1. State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Science, Shanghai 201203, China
2. Institute of Pediatrics of Children's Hospital and Biomedical Science, Fudan University, Shanghai 200032, China
3. Nanchang University College of Pharmacy, 461 Bayi Rd, Nanchang 330006, China
4. NMPA Key Laboratory for Quality Research and Evaluation of Pharmaceutical Excipients
# Equal contribution

This is an open access article distributed under the terms of the Creative Commons Attribution License ( See for full terms and conditions.
Yin W, Zhao Y, Kang X, Zhao P, Fu X, Mo X, Wan Y, Huang Y. BBB-penetrating codelivery liposomes treat brain metastasis of non-small cell lung cancer with EGFRT790M mutation. Theranostics 2020; 10(14):6122-6135. doi:10.7150/thno.42234. Available from

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EGFR TKI therapy has become a first-line regimen for non-small cell lung cancer (NSCLC) patients with EGRF mutations. However, there are two big challenges against effective therapy--the secondary EGFR mutation-associated TKI resistance and brain metastasis (BMs) of lung cancer. The BMs is a major cause of death for advanced NSCLC patients, and the treatment of BMs with TKI resistance remains difficult.

Methods: Tumor-associated macrophages (TAM) is a promising drug target for inhibiting tumor growth, overcoming drug resistance, and anti-metastasis. TAM also plays an essential role in regulating tumor microenvironment. We developed a dual-targeting liposomal system with modification of anti-PD-L1 nanobody and transferrin receptor (TfR)-binding peptide T12 for codelivery of simvastatin/gefitinib to treat BMs of NSCLC.

Results: The dual-targeting liposomes could efficiently penetrate the blood-brain barrier (BBB) and enter the BMs, acting on TAM repolarization and reversal of EGFRT790M-associated drug resistance. The treatment mechanisms were related to the elevating ROS and the suppression of the EGFR/Akt/Erk signaling pathway.

Conclusion: The dual-targeting liposomal codelivery system offers a promising strategy for treating the advanced EGFRT790M NSCLC patients with BMs.

Keywords: brain targeting delivery, tumor-associated macrophage, non-small cell lung cancer (NSCLC), drug resistance, tyrosine kinase inhibitors (TKI), EGFR T790M mutation