Oxygenation: Nanotechnological Strategies for Conquering Tumor Hypoxia in Photodynamic Therapy

Jingru Liang,1,2,* Xiujun Lai,1,* Yujia Mei,1,2 Xingyun Liu,1,2 Shunbo Wen,1,2 Yusheng Zhou,1,2 Furong Liu1,2 1Department of Pharmacy, The Affiliated Nanhua Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, People’s Republic of China; 2School of Pharmaceutical Science, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, People’s Republic of China*These authors contributed equally to this workCorrespondence: Furong Liu, Email Liufurong72@163.com Yusheng Zhou, Email yszhou08@126.comAbstract: Photodynamic therapy (PDT) is a clinically established treatment with high selectivity and minimal invasiveness. However, its efficacy against solid tumors is severely compromised by hypoxia, a hallmark of the tumor microenvironment (TME). Although conventional approaches, such as oxygen delivery and in situ oxygen generation, offer certain benefits, their passive and uncontrolled nature poses substantial challenges. This review explores alternative strategies to actively overcome tumor hypoxia, highlighting recent advances in nanotechnology that go beyond traditional oxygen replenishment methods. We focus on three main avenues for enhanced PDT: remodeling the hypoxic TME, circumventing intratumoral hypoxia, and harnessing hypoxia. Furthermore, we offer a forward-looking perspective on nanotechnology-mediated hypoxia modulation and discuss potential pathways for oxygen-optimized PDT in next-generation cancer therapy. This review provides valuable and clinically significant insights into the development of PDT. Keywords: photodynamic therapy, hypoxia, nanotechnology, tumor microenvironment