A Pt(IV)-Cluster-Nanobomb for Concurrent Activation of Triple Programmed Cell Death Pathways: A New Effective Method to Overcome Cisplatin Resistance

Abstract Activation of single programmed cell death (PCD) pathway frequently contributes to the development of cisplatin (CP)-resistance. Herein, we designed and synthesized a series of carrier-free Pt(IV) nano-prodrugs designated CSPNPs (6aNPs−6dNPs). These prodrugs integrate three functional components into a single entity: CP as the core PCD-initiator; disulfide-cinnamic acid (CA) derivatives as amplifiers; and hydrophobic chains for self-assembly. Enriched in tumors via enhanced permeability and retention effect, CSPNPs cleave disulfide bonds and reduce Pt(IV) in high-glutathione (GSH) tumor microenvironment, depleting GSH and releasing active Pt(II) and CA-derivatives. This multi-pronged intervention blocks GSH-dependent cytoprotective hub and synergistically triggers p53-mediated apoptosis, GPX4-related ferroptosis and copper-driven cuproptosis. Compared with CP, the optimal 6bNPs gained 78.7% tumor inhibition in 4T1 xenograft-bearing mice, increased intratumoral Pt-content by 13.5-fold and alleviated systemic toxicity. This study establishes a viable paradigm beyond conventional CP-based chemotherapy and offers a generalizable strategy to enhance the inherent multi-pathway bioactivity of traditional chemotherapeutics.