Tumor microenvironment-responsive self-assembling nanotherapeutics integrating chemo-, anti-angiogenic, and...

Area of Science:

• Biomedical Engineering
• Nanotechnology
• Oncology

Background:

• Triple-negative breast cancer (TNBC) presents significant treatment challenges due to a lack of targeted therapies and the toxicity of agents like doxorubicin (DOX).
• Current treatments are limited by poor tumor targeting and systemic side effects, necessitating innovative delivery systems.

Purpose of the Study:

• To develop a tumor microenvironment (TME)-responsive nanoplatform for targeted TNBC therapy.
• To integrate active tumor targeting, triggered drug release, anti-angiogenesis, and chemotherapy into a single system.
• To investigate the potential of targeting moesin (MSN) for TNBC-specific delivery.

Main Methods:

• Identification of an SML peptide with high TNBC binding affinity and exploitation of fibroblast activation protein-alpha (FAP-α) for TME-triggered release.
• Development of a self-assembled peptide-based nanocarrier (QGS@DOX) encapsulating doxorubicin.
• In vitro and in vivo evaluation of QGS@DOX for tumor targeting, drug release kinetics, therapeutic efficacy, and toxicity.

Main Results:

• QGS@DOX demonstrated enhanced tumor accumulation, prolonged circulation, and controlled DOX release.
• The nanoplatform effectively inhibited TNBC tumor growth and metastasis while significantly reducing doxorubicin-induced cardiotoxicity.
• Mechanistic studies showed suppression of epithelial-mesenchymal transition (EMT), induction of immunogenic cell death (ICD), and activation of the cGAS-STING pathway.

Conclusions:

• The developed QGS@DOX nanoplatform offers a promising strategy for precise, multimodal TNBC treatment by combining FAP-α responsiveness, SML-MSN targeting, and chemotherapy.
• This integrated approach effectively remodels the TME and presents a novel therapeutic avenue for TNBC.
• The study highlights the potential of targeting moesin (MSN) for TNBC-specific drug delivery.