Gold(I)-Loaded Nanomedicine for Liver Cancer: A Closed-Loop Strategy Integrating Ferritinophagy-Driven Ferroptosis and Immunotherapy.

The clinical translation of gold(I) pharmacophores for liver cancer is hindered by rapid deactivation, poor tumor selectivity, and off-target toxicity. To address these limitations, we engineered a tumor-targeting bovine serum albumin (BSA)-based nanoarchitecture loaded with a gold(I) complex, designated TEP NPs. As an integrated BSA-gold(I) nanoplatform, TEP NPs inherently induce ferritinophagy and leverage the enhanced permeability and retention (EPR) effect and pH-responsive release for TME-triggered gold(I) delivery. TEP NPs inhibit thioredoxin reductase (TrxR), disrupting redox homeostasis and inducing mitochondrial apoptosis. Simultaneously, TEP NPs activate NCOA4-mediated ferritinophagy, leading to ferritin degradation and a surge in labile iron that synergizes with TrxR inhibition to drive ferroptosis. This trimodal cell death triggers immunogenic cell death (ICD) and DAMPs release. In vivo, TEP NPs reprogram the tumor microenvironment by recruiting immune effectors, establishing a closed-loop of tumor killing and immune activation.