GSH-Triggered Nitric Oxide-Releasing Polycarbonate Nanoplatform for Synergistic Gas-Sonodynamic Antitumor Therapy

Sonodynamic therapy (SDT) emerges as a promising noninvasive modality for deep tumors but is hindered by the hypoxic tumor microenvironment and glutathione (GSH)-mediated reactive oxygen species (ROS) scavenging. Herein, we report a GSH-responsive nanoplatform fabricated from an mPEG-b-PMNC copolymer, enabling spatiotemporal codelivery of nitric oxide (NO) donors and the sonosensitizer chlorin e6 (Ce6) via self-assembled micelles. Upon exposure to elevated intracellular GSH, the micelles disintegrate to release NO and Ce6 selectively. The released NO attenuates hypoxia through downregulation of hypoxia-inducible factor-1α (HIF-1α) and synergizes with ultrasound-triggered Ce6-generated ROS to yield highly cytotoxic peroxynitrite (ONOO-). This integrated synergy substantially potentiates SDT outcomes, as evidenced by an IC50 of 1.935 μg/mL for mPEG-b-PMNC@Ce6 micelles under ultrasound, outperforming free Ce6 (4.808 μg/mL) and control mPEG-b-PCL@Ce6 (2.736 μg/mL). This polycarbonate-based strategy provides a novel approach for synergistic gas-sonosensitizer delivery, overcoming key limitations of conventional SDT for treating hypoxic tumors.