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Targeting miR-155 in triple negative breast cancer via CRISPR/Cas9 delivery using peptide-engineered extracellular vesicles

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Resumo:Triple negative breast cancer (TNBC) represents a heterogeneous and aggressive subtype of breast cancer, accounting for 10-20% of all cases. It is associated with a poor prognosis due to the absence of effective targetable biomarkers and high metastatic potential. Despite advances in cancer therapy, TNBC remains a challenging condition for clinicians, highlighting the need for novel therapies. Dysregulation of microRNAs (miRNAs) has been implicated in cancer progression, with miR-155, one of the most frequently overexpressed miRNAs in both solid and hematological cancers, being linked to breast cancer development. This study investigated the role of miR-155 in TNBC and explored its potential as a therapeutic target. miR-155 was found to be upregulated in multiple TNBC cell lines, and the CRISPR/Cas9 genome editing system was used to specifically disrupt miR-155 expression. This disruption led to significant effects on TNBC cell biology, including impaired cell proliferation, G2/M cell cycle arrest, reduced cell migration, and activation of the intrinsic apoptosis pathway. Additionally, to enhance CRISPR/Cas9 delivery, extracellular vesicles (EVs) were engineered using a TNBC-specific peptide identified in-house through phage display. These chemically modified EVs demonstrated significantly enhanced uptake by TNBC cells in vivo, confirming their targeted delivery capability. The EVs efficiently encapsulated the CRISPR/Cas9 plasmid, enabling precise gene editing in TNBC cells. Altogether, these findings provide a proof-of-principle for a targeted, precise, and effective delivery approach for CRISPR genome editing in TNBC tumors.
Autores principais:Ferreira, Débora
Outros Autores:Sousa, Diana Andrade; Da Silva, Catarina; Gandarela, Leonor B.; Sousa, Mariana Martins; Rodrigues, L. R.
Ano:2025
País:Portugal
Tipo de documento:outro
Tipo de acesso:acesso aberto
Instituição associada:Universidade do Minho
Idioma:inglês
Origem:RepositóriUM - Universidade do Minho

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