Photodynamic therapy (PDT) is regarded as one of the promising cancer treatment options. However, there is an undesirable impediment with this approach in that tumor tissues generally suffer from serious hypoxia, which significantly affects the efficiency of PDT and results in tumor progression and metastasis. In this work, we designed and synthesized a boron-based versatile nanoplatform (PEGylated BNSs-MA), in which Matrine (MA) was used as a chemotherapy drug to achieve a combination therapy with PDT via downregulating hypoxia-inducible factor-1alpha (HIF-1α) to alleviate tumor hypoxia and decreasing the expression of BCL-2 protein to inhibit tumor metastasis. Our in vitro and in vivo findings clearly revealed that the combination therapy was more effective than monotherapy. This study not only demonstrated the great potential of PEGylated BNSs-MA for cancer photodynamic ablation but also provided a new therapeutic strategy to overcome tumor hypoxia. This study was supported by the Guangdong Basic and Applied Basic Research Foundation (2019B1515120043), the Research Fund of University of Macau (File no. MYRG2019-00121-ICMS and MYRG2018-00207-ICMS) and the Science and Technology Development Fund, Macau SAR (File no. 0098/2020/A).