Bioactive PdPt nanosheets for hypoxia modulation-enhanced radiotherapy

Abstract

With the global rise in cancer incidence, the development of effective and safe therapeutic strategies remains an urgent priority. Although radiotherapy (RT) is widely used in clinical oncology, its therapeutic efficacy is often compromised by the hypoxic tumor microenvironment, which induces radioresistance. Therefore, alleviating tumor hypoxia to enhance radiosensitivity has emerged as a promising strategy for improving radiotherapeutic outcomes. Herein, we developed bovine serum albumin (BSA)-modified PdPt nanosheets (PdPt@BSA) with intrinsic catalytic activity, radiosensitizing capability, and photothermal properties for enhanced cancer therapy. PdPt@BSA effectively amplified X-ray-induced cellular damage, as evidenced by increased reactive oxygen species (ROS) generation, aggravated mitochondrial dysfunction, and enhanced DNA double-strand breaks. Notably, PdPt@BSA alleviated tumor hypoxia through catalytic oxygen generation, accompanied by the downregulation of hypoxia-inducible factor-1α (HIF-1α), thereby overcoming hypoxia-induced radioresistance and significantly enhancing the therapeutic efficacy of radiotherapy. In addition, PdPt@BSA exhibited strong near-infrared absorption and outstanding photothermal conversion efficiency, which further potentiated tumor radiosensitization under near-infrared irradiation. In vivo studies demonstrated that PdPt@BSA-based combination therapy markedly suppressed tumor growth with minimal systemic toxicity. Moreover, PdPt@BSA partially induced immunogenic cell death, suggesting their potential to activate antitumor immune responses. Overall, this work presents a PdPt nanosheet-based nanoplatform that integrates catalytic hypoxia modulation, radiosensitization, and photothermal enhancement, providing a promising strategy for improving cancer radiotherapy.