Recent advances in nanophotosensitizers for overcoming tumor hypoxia in photodynamic therapy

Photodynamic therapy (PDT) has garnered considerable attention due to its remarkable spatiotemporal selectivity, minimal invasiveness, and low potential for drug resistance, making it a widely utilized therapeutic modality for various tumors in clinical practice. However, the hypoxic tumor microenvironment (TME), resulting from accelerated tumor cell proliferation and inadequate oxygen (O₂) supply, significantly impedes the therapeutic efficacy of PDT. Furthermore, the O₂ consumption during PDT exacerbates tumor hypoxia, which in turn accelerates tumor progression and contributes to suboptimal therapeutic outcomes. To mitigate this challenge, recent advancements in nanotechnology have facilitated the development of nano-photosensitizers (nano-PSs) capable of alleviating hypoxic TME through a variety of strategies. This review provides an overview of recent advancements in PDT strategies aimed at overcoming tumor hypoxia, which encompass: (1) alleviating hypoxia, (2) utilizing hypoxia, (3) regulating the hypoxic TME, and (4) designing type-I PSs. Through a review of recent advancements, this work seeks to offer insights into the design of nano-PSs that can mitigate hypoxia-related limitations in PDT, while also highlighting future opportunities and challenges for clinical translation.