Fibroblast Activation Protein Alpha-Targeted Nanoparticles for Tumor Microenvironment Remodeling and Antitumor Therapy in Triple-Negative Breast Cancer.

Triple-negative breast cancer (TNBC) remains a highly aggressive subtype with limited treatment options and poor prognosis. While most therapies target tumor cells, the tumor microenvironment (TME), particularly cancer-associated fibroblasts (CAFs), plays a key role in tumor progression, therapy resistance, and immune suppression. We developed NP-FAP-DOX, a mesoporous silica nanoparticle-based nanodevice loaded with doxorubicin and functionalized with a fibroblast activation protein alpha (FAP-α) ligand peptide for selective binding to FAP-α-positive CAFs. FAP-α targeting ability and cytotoxic effect were assessed in TNBC cells, patient-derived CAFs, and patient-derived organoids (PDOs). In vivo efficacy was evaluated in the murine orthotopic TNBC 4T1 allograft model, assessing tumor growth inhibition, toxicity, CAFs depletion, extracellular matrix degradation, apoptosis induction, and TME-associated cellular and stromal changes. NP-FAP-DOX exhibited controlled drug release, selective binding to FAP-α, and cytotoxicity in TNBC cells, patient-derived CAFs, and PDOs. In vivo, NP-FAP-DOX reduced tumor growth, depleted CAFs, degraded the extracellular matrix, induced apoptosis, increased lymphocyte infiltration, and decreased M2-like macrophages. Compared with free doxorubicin, NP-FAP-DOX enhanced therapeutic efficacy while reducing cardiotoxicity and systemic side effects. These findings highlight NP-FAP-DOX as a promising nanomedicine strategy for TNBC, integrating tumor inhibition, TME remodeling, and immune activation, with strong potential for clinical translation.