Cisplatin-Doped Black Phosphorus Nanomedicines Overcome Platinum-Based Anticancer Drug Resistance via Piezoelectric-Mediated Adaptive Homeostasis Disruption.

The clinical efficacy of platinum-based chemotherapeutics is frequently diminished by the emergence of resistance during prolonged treatment. Cisplatin (DDP)-resistant tumors adapt to chemotherapeutic stress by establishing a new state of adaptive homeostasis that sustains cellular survival under drug pressure, albeit at the expense of high metabolic burden and acquired vulnerability. Exploiting this intrinsic weakness, we designed a DDP-doped black phosphorus (BP) nanomedicine protected by polydopamine coating (DDP-BP@PDA) that synergistically delivered DDP and piezoelectric BP to precisely disrupt resistance homeostasis and thereby reverse DDP resistance. DDP-BP@PDA altered the intracellular uptake pathway of DDP and disrupted the redox balance of resistant cells via piezocatalysis. Concurrently, piezoelectric polarization enhanced the peroxidase-like activity via electron injection, leading to the generation of substantial reactive oxygen species (ROS). This ROS burst compromised the integrity of the endoplasmic reticulum (ER) membrane and exacerbated the protein-folding burden, thereby amplifying ER stress. Mechanism study reveals that excessive ER stress downregulated the expression of DNA repair proteins, making resistant cells highly sensitive to DDP-induced DNA damage. Through these synergistic effects, DDP-BP@PDA disrupted the adaptive homeostasis of DDP-resistant cells, thereby significantly inhibiting the progression of DDP-resistant tumors. This study establishes a promising therapeutic strategy to combat DDP-resistance via piezoelectric-driven disruption of adaptive homeostasis.