Butyrylated PGAM5‐Triggered and GSH‐Responsive Cysteine Polymer Nanoparticles for CBL0137 Delivery to Enhance Necroptosis in Prostate Cancer

Prostate cancer (PCa) is characterized by significant metabolic heterogeneity, particularly in glutathione (GSH) metabolism. Elevated GSH metabolism is closely linked to PCa progression, therapeutic resistance, and poor clinical outcomes. Recent studies have highlighted the impact of protein butyrylation on cancer biology, although related therapeutic strategies remain limited. Herein, we utilized a cysteine-based, GSH-responsive polymer (Cys8E) to deliver a broad-spectrum antitumor agent CBL0137. Exploiting high GSH levels in PCa cells, the resulting CBL0137-loaded nanoparticles (Cys8E@CBL NPs) achieved targeted and efficient intracellular delivery and enhanced tumor-killing efficacy. Mechanistic investigations revealed that upon internalization by tumor cells, Cys8E NPs perturbed butyrate-associated metabolic homeostasis, as reflected by altered abundance of related metabolic enzymes and increased intracellular protein butyrylation levels. This metabolic remodeling was accompanied by enhanced lysine-95 butyrylation of PGAM5, which promoted necroptosis. Collectively, these findings define Cys8E@CBL NPs as a redox-responsive formulation in which the carrier contributes to therapy not only by improving CBL0137 delivery but also by reshaping butyrate-associated metabolism. This process promotes PGAM5 K95 butyrylation and strengthens necroptotic tumor cell killing. These results extend the design rationale of nanomedicine from passive payload transport toward active regulation of metabolism-dependent post-translational signaling in prostate cancer.