What type of study is this?

This is a In Vitro Study study (also classified as: Animal Study).

August 21, 2025Open Access

Mesenchymal stem cells expressing CES1 and soluble TRAIL activate CPT-11 and induce apoptosis in lung cancer brain metastatic lesions

DKDong Oh KimKorea Research Institute of Chemical Technology EJEun Hyang JangKyung Hee University YKYong-Nam KwonSungkyunkwan University

Key Points

Combination therapy significantly suppressed tumor growth in lung cancer brain metastasis models, and demonstrated efficacy through targeted drug activation.
Modified WJ-MSCs maintained stemness while secreting high levels of functional soluble TRAIL and CES1, enabling apoptosis in tumors.
In vivo assessments utilized bioluminescent imaging and immunohistochemistry to evaluate therapeutic impact and safety profiles.
This approach offers a promising non-viral platform for personalized treatment targeting lung cancer brain metastases, with minimal off-target effects.

Abstract

Abstract To develop a novel therapeutic strategy for lung cancer brain metastases by leveraging the tumor-tropic properties of genetically engineered Wharton’s Jelly-derived mesenchymal stem cells (WJ-MSCs) as vehicles for dual-agent gene therapy across the blood-brain barrier. WJ-MSCs were transiently engineered using lipid nanoparticle (LNP) technology to co-express soluble TRAIL (sTRAIL) and the prodrug-activating enzyme carboxylesterase 1 (CES1). In vitro analyses assessed transfection efficiency, therapeutic protein expression, apoptosis induction, and maintenance of stemness. Tumor-homing capacity was evaluated via EGFP labeling and intracerebral tracking. Therapeutic efficacy was tested in subcutaneous and intracerebral lung cancer xenograft models using bioluminescent imaging, histopathology, and immunohistochemistry. In vivo treatment included intraperitoneal CPT-11 administration to assess synergy between CES1-mediated prodrug activation and sTRAIL-induced apoptosis. Modified WJ-MSCs exhibited preserved stem cell characteristics and strong tropism toward brain tumor sites. They secreted high levels of functional sTRAIL and CES1, enabling local activation of CPT-11 into SN-38 and inducing apoptosis through death receptor signaling (DR4/DR5). Combination therapy with WJ-MSCs-CES1.sTRAIL and CPT-11 significantly suppressed tumor growth in lung cancer brain metastasis models compared to control groups. The approach demonstrated selective cytotoxicity, minimal off-target effects, and favorable safety profiles. This study establishes a non-viral, transient gene delivery platform using autologous WJ-MSCs for dual-action gene therapy in lung cancer brain metastases. The combined use of CES1 and sTRAIL and enables precise tumor targeting and drug activation, offering a promising avenue for personalized, stem cell–based treatment strategies to improve outcomes in patients with brain metastatic lung cancer.

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