Copper-Doped Nanoscale Covalent Organic Polymer for Augmented Photo/Chemodynamic Synergistic Therapy and Immunotherapy

Due to the specific tumor microenvironment (TME) and immunosuppressive state of cancer cells, conventional antitumor therapies face severe challenges, such as high rates of recurrence and metastasis. Herein, Cu-PPT nanoparticles were synthesized based on copper acetate, p-phenylenediamine, and 5,10,15,20-tetra-(4-aminophenyl)porphyrin via oxidative coupling reaction for the first time, and the resultant product was used for synergistic photothermal therapy (PTT), photodynamic therapy (PDT), and chemodynamic therapy (CDT). The polymer nanoparticles exhibited excellent photodynamic and photothermal effect with a photothermal conversion efficacy of 40.1% under 650 and 808 nm laser irradiation, respectively. Encapsulated Cu(I)/Cu(II) ions permitted Cu-PPT with glutathione (GSH) peroxidase-mimicking, catalase-mimicking, and Fenton-like activity to regulate TME. Depletion of overexpressed GSH would reduce antioxidant capacity, generated O₂ could relieve hypoxia for enhancing PDT, and hyperthermia from PTT could promote the yield of ·OH. This multifunctional nanosystem with cascade reactions could inhibit tumor growth and activate immune responses effectively. By further combining with antiprogrammed death-ligand 1 (anti-PD-L1) checkpoint blockade therapy, distant tumor growth and cancer metastasis were successfully suppressed.