Combined photothermal and photodynamic therapy enhances ferroptosis to prevent cancer recurrence after surgery using nanoparticle-hydrogel composite

Post-surgical cancer recurrence and metastasis are primary contributors to cancer mortality. To effectively eliminate residual tumor cells, a composite hydrogel consisting of polyacrylic acid (PAA) and Pluronic F127 (F127) was developed for post-surgical cancer treatment. The hydrogel incorporates zinc-centered carbon nanododecahedrons (ZCND) and erastin. ZCND demonstrates both photodynamic therapy (PDT) and photothermal therapy (PTT) performance, which downregulate heat shock proteins 70 (HSP70) and glutathione peroxidase 4 (GPX4) to enhance the ferroptosis efficacy triggered by erastin. The synergistic effect of PDT and PTT results in reduced intracellular HSP70 levels, destabilizing GPX4 and amplifying ferroptosis effects. Additionally, PDT and PTT generate substantial reactive oxygen species, which deplete intracellular reduced glutathione, thereby increasing oxidative stress and promoting tumor cell death. Mice with resected tumors exhibit no significant recurrence or mortality after combined PDT, PTT and erastin treatment. In vitro and in vivo studies confirm that the ZCND-erastin/PAA:F127 hydrogel effectively suppresses tumor recurrence post-resection. Collectively, our findings offer innovative insights into the synergistic application of ferroptosis therapy and the prevention of post-surgical tumor recurrence.