Targeted Degradation of HER2-Positive Breast Cancer via Engineered Exosomes: A Multi-Omics Analysis of Tumor Microenvironment Remodeling and Therapeutic Efficacy

• • Exo-HER2 achieved a 72.4% reduction in HER2 phosphorylation (p < 0.001) and a 3.2-fold increase in apoptosis in HER2-positive SK-BR-3 cells, outperforming trastuzumab monotherapy and addressing resistance mechanisms. • • In an orthotopic xenograft model, systemic Exo-HER2 administration led to a 68.5% tumor volume reduction (p < 0.01) and a 45.6% decrease in Ki-67 proliferation index, demonstrating potent in vivo efficacy. • • The engineered exosomes exhibited 8.7-fold higher blood-brain barrier penetration than free trastuzumab, a critical advantage for treating brain metastases in HER2-positive breast cancer. • • Multi-omics analysis revealed a 2.4-fold increase in CD8+ T cell infiltration and a 1.8-fold reduction in M2 macrophage polarization, indicating that Exo-HER2 remodels the tumor microenvironment towards an immunostimulatory phenotype.