The hypoxic nature of solid tumors limits the efficacy of radiotherapy (RT) and leads to radiation resistance. Hypoxic radiosensitizers can enhance tumor radiosensitivity by mimicking the effects of oxygen, but their efficacy has been limited by the heterogeneous oxygen distribution in tumor tissue. Herein, a multimodal therapeutic nanoplatform fabricated by co-encapsulation of chlorin e6 and tirapazamine (TPZ) with an amphiphilic polymeric conjugate of cisplatin (CDDP) and metronidazole is reported. This platform could kill the tumor periphery cells by the deeply penetrated oxygen-consuming sonodynamic therapy and unify the heterogeneously hypoxic context simultaneously, which then actuate the release and activation of the loaded TPZ. TPZ could further sensitize RT along with CDDP and metronidazole residues under the resultant hypoxic condition, which significantly decreases the radiation dosage required to cause massive cell damage. Except for the significantly suppressed tumor growth and metastasis caused by the multimodal therapeutic nanoplatform, its hypoxia-directed feature also endows it with excellent safety.

Chemoradiotherapy (CRT) is the most accepted treatment for locally advanced pancreatic ductal adenocarcinoma (PDAC) and can significantly improve the R0 resection rate. However, there are few long‐term survivors after CRT. Although some polymer nanoparticles have shown potential in alleviating the dose‐limiting toxicity and assisting the chemotherapy of PDAC, there are few efficient nanosensitizers (NS) available for CRT of this malignancy, especially in the context of its hypoxic nature. Herein, based on the biological features of PDAC, a γ‐glutamyl transpeptidase (GGT)/glutathione (GSH)/hypoxia triple‐responsive prodrug NS to overcome the biological barrier and microenvironmental limitations confronted by CRT in PDAC is developed. Due to triple‐responsiveness, deep tumor penetration, GSH/hypoxia‐responsive drug release/activation, and hypoxia‐induced chemoradio‐sensitization can be simultaneously achieved with this NS. As a result, tumor shrinkage after CRT with this NS can be observed in both subcutaneous and orthotopic PDAC models, foreshadowing its potential in clinical neoadjuvant CRT.