Gelatin Methacryloyl Xerogel Puncture Implants Loaded with Cu_0.5Mn_2.5O₄ Nanoparticles Synergizes Cuproptosis and STING Activation for Enhanced Breast Cancer Immunotherapy

The immunosuppressive niche of the breast cancer microenvironment and the vascular basement membrane significantly hinder the efficacy of nanoparticle-based antitumor immunotherapy delivered via the vascular system. This study describes the design of a puncture-delivered tumor implant, utilizing a photo-cross-linked gelatin methacryloyl hydrogel as the matrix, loaded with Cu_0.5Mn_2.5O₄ nanoparticles (CMO NPs) and monomethyl fumarate (MMF), enabling the sustained release of nanoparticles through matrix metalloproteinase-responsive degradation. Mechanistically, CMO NPs induce cuproptosis and immunogenic cell death (ICD) in tumor cells, while synergizing with MMF to trigger substantial mtDNA release into the cytosol. Subsequently, the liberated mtDNA synergizes with Mn²⁺ to activate the cGAS-STING signaling pathway, which cooperates with ICD to enhance CD8⁺ T cell infiltration and increase the levels of related inflammatory factors in the breast tumor microenvironment. Notably, the implant significantly enhances the efficacy of αPD-1 therapy by modulating PD-L1/PD-1 expression. In summary, the implant designed in this study provides a practical strategy for nanoparticle delivery and immunotherapy of breast cancer.