Precise HER2 Protein Degradation via Peptide-Conjugated Photodynamic Therapy for Enhanced Breast Cancer Immunotherapy.

Abstract

Breast cancer, the most prevalent malignancy among women, frequently exhibits high HER2 expression, making HER2 a critical therapeutic target. Traditional treatments combining the anti-HER2 antibody trastuzumab with immunotherapy face limitations due to toxicity and tumor microenvironment immunosuppression. This study introduces an innovative strategy combining HER2-targeting peptides with the photosensitizer (PSs) pyropheophorbide-a (Pha) via a gelatinase-cleavable linker, forming self-assembling nanoparticles. These nanoparticles actively target breast cancer cells and generate reactive oxygen species (ROS) under near-infrared light, effectively degrading HER2 proteins. Upon internalization, the linker is cleaved, releasing Pha-PLG and enhancing intracellular photodynamic therapy (PDT). The Pha-PLG molecules self-assemble into nanofibers, prolonging circulation, boosting immune induction, and activating CD8⁺ T cells, thus promoting a robust anti-tumor immune response. In vivo, studies confirm superior biosafety, tumor targeting, and HER2 degradation, with increased cytotoxic T cell activity and improved antitumor immunity. This integrated strategy offers a promising new avenue for breast cancer treatment.