Dendrimer-Mediated\nGeneration of a Metal-Phenolic\nNetwork for Antibody Delivery to Elicit Improved Tumor Chemo/Chemodynamic/Immune\nTherapy

To simplify the composition and improve the efficacy\nof metal-phenolic\nnetwork (MPN)-based nanomedicine, herein, we designed an MPN platform\nto deliver programmed death ligand-1 (PD-L1) antibody (anti-PD-L1)\nfor combined tumor chemo/chemodynamic/immune therapy. Here, generation\n5 poly(amidoamine) dendrimers conjugated with gossypol (Gos) through\nboronic ester bonds were used as a synthetic polyphenol to coordinate\nMn<sup>2+</sup>, and then complexed with anti-PD-L1 to obtain the\nnanocomplexes (for short, DPGMA). The prepared DPGMA exhibited good\nwater dispersibility with a hydrodynamic size of 166.3 nm and tumor-microenvironment-responsive\ndrug release behavior. The integration of Gos and Mn<sup>2+</sup> within\nthe DPGMA resulted in significant tumor inhibition and immunogenic\ncell death activation through Gos-mediated chemotherapy and Mn<sup>2+</sup>-catalyzed chemodynamic therapy, respectively, thereby leading\nto significant dendritic cell maturation due to the role of Mn<sup>2+</sup> played to mediate the activation of the stimulator of interferon\ngenes (STING) pathway. Moreover, the complexed anti-PD-L1 promoted\nthe recognition and uptake of nanocomplexes by PD-L1-overexpressed\ntumors through antibody targeting, thereby achieving combinational\nchemo/chemodynamic/immune therapy in a mouse melanoma model, where\nthe immunotherapy modes combined three parts of activation via chemotherapy/CDT-mediated\nICD, Mn<sup>2+</sup>-mediated STING activation, and antibody-mediated\nimmune checkpoint blockade. With the Mn<sup>2+</sup>-endowed <i>r</i><sub>1</sub> relaxivity (1.38 mM<sup>–1</sup> s<sup>–1</sup>), the DPGMA nanocomplexes can also be used for tumor\nMR imaging. The designed dendrimer-mediated MPN platform may be developed\nas an advanced nanomedicine to tackle other cancer types.