Nanoparticle Enabled Copper Delivery for Tumor Selective Induction of Cuproptosis

One of oncology's most urgent challenges is the creation of tumor-selective treatment modalities, especially for chemoresistant and refractory cancers. A newly discovered copper-dependent type of controlled cell death called cuproptosis takes advantage of the metabolic weaknesses of cancer cells that have increased expression of lipoylated proteins and mitochondrial respiration. In contrast to ferroptosis, necroptosis, or apoptosis, cuproptosis is caused by the destabilisation of iron-sulfur cluster proteins and the aggregation of lipoylated mitochondrial proteins, which results in selective tumour cell death and proteotoxic stress. The regulated and tumor-selective administration of copper ions is a significant obstacle to the therapeutic exploitation of cuproptosis since systemic copper dysregulation can cause damage in healthy tissues. By increasing tumour accumulation, allowing regulated release, and reducing systemic exposure, nanoparticle-based delivery systems present a viable way to get around this restriction. In this work, we used a core–shell design with a biodegradable polymeric core, polyethylene glycol (PEG) coating, and surface-conjugated targeting ligands (RGD peptides) to create tumor-targeted copper-loaded nanoparticles (Cu-NPs) that improve tumour tropism. The nanoparticles were tailored to release copper in the acidic tumour microenvironment in response to pH. Strong cuproptotic activity was shown in vitro in several tumour cell lines with significant mitochondrial oxidative phosphorylation, as shown by lipoylated protein aggregation, decreased ferredoxin levels, and compromised mitochondrial respiration, but non-transformed cells were spared. Cu-NPs selectively accumulated in xenograft tumours in vivo, causing approximately 75% tumour growth inhibition with no damage. Proteotoxic stress, reduced iron-sulfur cluster stability, and mitochondrial malfunction all supported cuproptosis as the main mechanism of cell death, according to mechanistic research. All things considered, this work shows that copper distribution via nanoparticles can specifically take advantage of tumour metabolic weaknesses to cause cuproptosis, providing a potential treatment approach for refractory malignancies. The study emphasizes the potential of combining nanotechnology with metabolic-targeted oncology and lays the groundwork for the translational development of cuproptosis-targeted treatments.