Pathology-inspired nanotherapeutics improve tumor penetration and glutathione depletion to potentiate cuproptosis in peritoneal metastases

Colorectal cancer peritoneal metastasis (CRC-PM) is a prevalent and intractable late-stage complication of colorectal cancer with extremely poor prognosis. Inspired by distinctive pathology of PM tumors from CRC-PM patients, including upregulation of ferredoxin 1 (FDX1) and lipoyl synthase (LIAS), high glutathione (GSH) level and dense stroma, a cuproptosis-potentiating nanotherapeutics (designated PGd-MC) was rationally designed with efficient tumor-penetrating and GSH-depleting ability, aiming to amplify cuproptosis-mediated cell death for CRC-PM treatment. PGd-MC exhibited robust intratumoral penetration in murine and patient-derived xenograft (PDX)-PM models, and produced a 72.68% and 81.82% inhibition of PM progression, ultimately resulting in a 1.98-fold and 1.72-fold survival prolongation, outperforming the clinical standard FOLFIRI regimen. Collectively, the pathology-inspired PGd-MC provides a promising therapeutic strategy for CRC-PM treatment.