Copper-based hollow mesoporous nanogenerator with reactive oxygen species and reactive nitrogen species storm generation for self-augmented immunogenic cell death-mediated triple-negative breast cancer immunotherapy.

Although nanotheranostics have great potential in tumor immunotherapy, their effectiveness is often hindered by low immunogenic cell death (ICD) and inactivated immune responses in the tumor immunosuppressive microenvironment (TIME). Such vulnerability may lead to metastasis or recurrence, especially in triple-negative breast cancer (TNBC). Addressing this challenge, the study presents a multimodal immunotherapeutic approach using a self-enhanced ICD copper (Cu)-based hollow nanogenerator. This nanogenerator is activated by a near-infrared (NIR) laser to produce reactive oxygen species (ROS) and reactive nitrogen species (RNS) storms. Specifically, the nitric oxide (NO) donor l-Arginine (l-Arg) is loaded into hollow mesoporous Cu sulfide nanoparticles (HCuSNPs) with inherent NIR absorption and coated with tumor-targeting peptides (RGD), forming l-Arg@HCuSNPs-PEG-RGD (AHPR). In vitro and in vivo experiments demonstrate that AHPR can induce tumor thermal ablation, cuproptosis, and the generation of peroxynitrite anions (ONOO-) under NIR laser irradiation, resulting in multiple antitumor effects. Additionally, the nanogenerator enhances ICD through mechanisms such as mild-photothermal therapy (mPTT), cuproptosis, and ONOO- production, promoting immune cell infiltration and activation, and converting 'cold' tumors into 'hot' ones. By combining AHPR with the immune checkpoint inhibitor anti-programmed cell death protein ligand-1 antibody (αPD-L1), the study significantly improves the immunotherapy response rate in TNBC, offering a promising strategy to enhance TNBC immunotherapy efficacy.