Dendrimer-Mediated Generation of a Metal-Phenolic Network for Antibody Delivery to Elicit Improved Tumor Chemo/Chemodynamic/Immune Therapy.

To simplify the composition and improve the efficacy of metal-phenolic network (MPN)-based nanomedicine, herein, we designed an MPN platform to deliver programmed death ligand-1 (PD-L1) antibody (anti-PD-L1) for combined tumor chemo/chemodynamic/immune therapy. Here, generation 5 poly(amidoamine) dendrimers conjugated with gossypol (Gos) through boronic ester bonds were used as a synthetic polyphenol to coordinate Mn, and then complexed with anti-PD-L1 to obtain the nanocomplexes (for short, DPGMA). The prepared DPGMA exhibited good water dispersibility with a hydrodynamic size of 166.3 nm and tumor-microenvironment-responsive drug release behavior. The integration of Gos and Mn within the DPGMA resulted in significant tumor inhibition and immunogenic cell death activation through Gos-mediated chemotherapy and Mn-catalyzed chemodynamic therapy, respectively, thereby leading to significant dendritic cell maturation due to the role of Mn played to mediate the activation of the stimulator of interferon genes (STING) pathway. Moreover, the complexed anti-PD-L1 promoted the recognition and uptake of nanocomplexes by PD-L1-overexpressed tumors through antibody targeting, thereby achieving combinational chemo/chemodynamic/immune therapy in a mouse melanoma model, where the immunotherapy modes combined three parts of activation via chemotherapy/CDT-mediated ICD, Mn-mediated STING activation, and antibody-mediated immune checkpoint blockade. With the Mn-endowed relaxivity (1.38 mM s), the DPGMA nanocomplexes can also be used for tumor MR imaging. The designed dendrimer-mediated MPN platform may be developed as an advanced nanomedicine to tackle other cancer types.