Abstract: With the increasing of morbidity and mortality, cancer has become one of the leading causes of death worldwide. Photodynamic therapy (PDT) kills cancer cells by using reactive singlet oxygen (¹O₂) which is produced from photosensitizer by light activation, and has been widely utilized for many localized and superficial cancer treatments over the past four decades. The three major components of PDT are light, photosensitizer, and tissue oxygen. In PDT treatment, oxygen depletion and inherent hypoxia microenvironment in solid tumors may lead to further hypoxia, which in turn can hinder PDT efficacy. However, photothermal therapy (PTT) is not affected by the hypoxic environment, and has gained widespread attention owing to its noninvasive and low toxicity. Polydopamine nanoparticles (PDANPs) were utilized as a PTT agent for tumor treatment because of its good biocompatibility and high photothermal conversion efficiency. Here, we created a PDT-PTT system by grafting perfluorocarbon and photosensitizer into the hyaluronic acid (HA) chains and loading the PDANPs (Ac-HA-PFC-Pba-PDANPs). This PDT-PTT system consisted of a PDANPs core and a fluorinated HA photosensitizer shell. The synthesized Ac-HA-PFC-Pba-PDANPs had a relatively narrow particle size distribution (around 160 nm), and can be easily endocytosed by cancer cells. Furthermore, an efficient photothermal conversion function for PTT was also shown in the Ac-HA-PFC-Pba-PDANPs system. It raised up to 45 ℃ to kill cancer cells in a short time. With the excellent photothermal conversion ability of PDANPs, the high oxygen affinity of perfluorocarbon segments and the tumor targeting of HA, this system provides superior therapeutic efficacy against cancer cells. The anti-tumor effect was significantly improved, which was confirmed by cytotoxicity test and cell uptake studies. This novel nanoparticle provides a promising approach for synergetic PDT-PTT of hypoxic tumors.