Fibroblast Activation Protein Alpha-Targeted Nanoparticles for Tumor Microenvironment Remodeling and Antitumor...

Area of Science:

• Biomedical Engineering
• Nanomedicine
• Oncology

Background:

• Triple-negative breast cancer (TNBC) is aggressive with limited therapeutic options.
• The tumor microenvironment (TME), including cancer-associated fibroblasts (CAFs), significantly impacts TNBC progression and treatment resistance.
• Targeting CAFs offers a potential strategy to overcome TNBC challenges.

Purpose of the Study:

• To develop and evaluate NP-FAP-DOX, a nanodevice targeting FAP-α-positive CAFs in TNBC.
• To assess the in vitro and in vivo efficacy of NP-FAP-DOX in TNBC models.
• To investigate the impact of NP-FAP-DOX on tumor growth, TME, and systemic toxicity.

Main Methods:

• NP-FAP-DOX was engineered using mesoporous silica nanoparticles loaded with doxorubicin and functionalized with a FAP-α ligand peptide.
• In vitro studies included TNBC cells, patient-derived CAFs, and patient-derived organoids (PDOs) to assess drug release, targeting, and cytotoxicity.
• In vivo efficacy was evaluated in a murine orthotopic TNBC allograft model, analyzing tumor growth, CAFs depletion, ECM degradation, apoptosis, and immune cell infiltration.

Main Results:

• NP-FAP-DOX demonstrated controlled drug release, selective binding to FAP-α-positive CAFs, and potent cytotoxicity.
• In vivo studies showed significant tumor growth inhibition, CAFs depletion, extracellular matrix degradation, and increased lymphocyte infiltration.
• NP-FAP-DOX enhanced therapeutic efficacy compared to free doxorubicin, with reduced cardiotoxicity and systemic side effects.

Conclusions:

• NP-FAP-DOX represents a promising nanomedicine strategy for TNBC, effectively inhibiting tumor growth and remodeling the TME.
• The nanodevice integrates tumor inhibition, TME modulation, and immune activation, suggesting strong potential for clinical translation.
• Targeted delivery to CAFs offers a novel approach to improve TNBC treatment outcomes.