Adaptive dual-responsive nanocapsules for precision ferroptosis-driven and chemotherapy-enhanced tumor ablation

Tumors increasingly threaten human health, with rising incidence and mortality rates. Treatment complexity, including individual differences and tumor molecular characteristics, limits clinical application potential. Ferroptosis, a new strategy for tumor treatment, has stirred much interest. However, the dense properties and unique physiological environment of tumor tissues limit the ability of ferroptosis agents to work inside tumors. In this study, intelligent temperature and pH dual-responsive nanocapsules were designed for tumor therapy. The nanocapsules leverage the unique physiological environment of tumors, where both acidity and temperature can be exploited to trigger drug release. The core materials of the nanocapsules are a polylactic acid-glycolic acid copolymer and poly(N-isopropyl acrylamide), which ensure biocompatibility and responsiveness to the tumor microenvironment. These nanocapsules encapsulate amorphous iron nanoparticles as ferroptosis agents and tirapazamine as a chemotherapeutic drug, enabling a combination therapy approach. Once introduced into the tumor, the nanocapsules change size in response to the local acidic and thermal conditions, releasing their payload. This targeted approach enhances drug delivery efficiency, reduces toxicity to surrounding healthy tissues, and promotes ferroptosis in tumor cells. The study demonstrated the nanocapsules’ ability to inhibit tumor growth both in vitro and in vivo while maintaining excellent biocompatibility and biosafety, making it a promising candidate for advanced cancer therapies.