Thermoresponsive, Size-Tunable Hybrid Nanomicelles to Alleviate Tumor Hypoxia and Enhance Chemo-Photothermal Synergy Therapy of Cancer

Nanomedicines with a size of approximately 200 nm preferentially accumulate at the tumor peripheries but exhibit limited penetration into deeper hypoxic regions. To overcome this, we engineered near-infrared (NIR) light-triggered, size-tunable nanomicelles (Au@PtNRs/DOX-M) to enhance tumor accumulation and penetration, while alleviating hypoxia. Dumbbell-shaped platinum-deposited gold nanorods (Au@PtNRs), with a high photothermal conversion efficiency (68.44%), were integrated into thermoresponsive, doxorubicin (DOX)-loaded nanomicelles. Upon NIR irradiation, Au@PtNRs induced light-to-heat conversion, disassembling micelles into ultrasmall micelles for enhanced tumor penetration and on-demand DOX release. Concurrently, Pt nanoparticles catalyzed the decomposition of reactive oxygen species (ROS) to mitigate ROS-induced damage to adjacent healthy cells, and scavenged the elevated H 2 O 2 within tumors, generating abundant oxygen to reoxygenate the hypoxic microenvironment. This study establishes an efficient, size-tunable nanomicelle platform for enhancing hypoxia-impeded deep penetration of nanomedicines and offers a promising strategy for synergistic chemo-photothermal therapy, achieving tumor inhibition rates of up to 99% in MCF-7 tumor-bearing mice.