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Engineered Nanobody-Bearing Extracellular Vesicles Enable Precision Trop2 Knockdown in Resistant Breast Cancer.
Jassy Mary S Lazarte1, Mounika Aare1, Sandeep Chary Padakanti1
1Institute of Public Health, College of Pharmacy and Pharmaceutical Sciences, Florida A&M University, Tallahassee, FL 32307, USA.
Pharmaceutics
|October 29, 2025
Summary
Engineered extracellular vesicles (EVs) expressing a nanobody against Trop2 (NB60 E) effectively target and reduce Trop2 expression in breast cancer cells. This novel therapy shows potent anti-cancer effects by inhibiting growth, invasion, and angiogenesis, with rapid clearance from the system.
Area of Science:
- Biotechnology and Nanomedicine
- Oncology
- Molecular Biology
Background:
- Trophoblast cell surface antigen 2 (Trop2) is overexpressed in many epithelial cancers, making it a key therapeutic target, especially in breast cancer.
- Current therapeutic strategies require enhanced targeting mechanisms to effectively block Trop2 expression in tumors.
Purpose of the Study:
- To develop and evaluate extracellular vesicles (EVs) engineered to express a nanobody against Trop2 (NB60 E) for targeted cancer therapy.
- To assess the efficacy of NB60 E in reducing Trop2 expression, inhibiting cancer cell viability, and blocking downstream signaling pathways in breast cancer models.
Main Methods:
- Designed a plasmid construct to express Trop2-targeting nanobodies (NB60) on EVs derived from HEK293T cells.
- Investigated the potency of NB60 E to reduce Trop2 expression and cell viability in letrozole-resistant breast cancer cells (LTLT-Ca, MDA-MB-468) using MTT assays and Western blotting.
- Analyzed the impact of NB60 E on cytokine production (IL-6, TNF-α, IL-2) in Jurkat T cells via ELISA and assessed angiogenic capacity.
Main Results:
- NB60 E significantly reduced surface Trop2 expression in MDA-MB-468 (23.5%) and LTLT-Ca (61.5%) cells.
- NB60 E markedly reduced LTLT-Ca cell viability (52.8%) and downregulated key oncogenic pathways (p-ERK1/2, cyclin D1, p-STAT3, vimentin).
- In vivo studies demonstrated rapid, tumor-selective accumulation of NB60 E with efficient systemic clearance and significant Trop2 reduction in xenografts.
Conclusions:
- Engineered NB60 E-grafted EVs represent a novel, targeted therapy for Trop2-enriched breast cancers, effectively silencing growth and invasion pathways.
- This therapy demonstrates potent anti-tumor effects by blocking angiogenesis and modulating cytokine signaling, with the advantage of self-clearing biomimetic carriers.
- NB60 E shows significant potential as an anti-cancer agent for letrozole-resistant and other Trop2-expressing malignancies.
