Hypoxia-responsive self-assembled nanoparticles for reprogramming tumor-associated macrophages into an anti-tumor M1 phenotype in breast cancer.

The tumor microenvironment is characterized by hypoxia, resulting mainly from aberrant vascularization and insufficient blood perfusion. Under such hypoxic conditions, tumor-associated macrophages (TAMs) preferentially polarize toward an immunosuppressive M2-like phenotype, which promotes immune evasion and accelerates tumor progression. Reprogramming these M2-like TAMs into an anti-tumor M1 phenotype represents a promising therapeutic strategy, yet it remains a substantial challenge. In this study, we developed nanoparticles functionalized with mannose and an MMP-2-responsive PLGVRGD peptide. These nanoparticles undergo self-assembly in the presence of matrix metalloproteinase-2 (MMP-2), which is highly expressed in hypoxic tumor regions. The high-density mannose residues on the nanoparticle surface facilitate efficient binding to M2-like TAMs and promote their repolarization to the M1 phenotype. Moreover, the resulting system exhibits enhanced tumor tissue penetration and effectively reverses the immunosuppressive tumor microenvironment, supporting its potential as a targeted nanotherapeutic strategy for breast cancer.