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 Mn²⁺, 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 Mn²⁺ within the DPGMA resulted in significant tumor inhibition and immunogenic cell death activation through Gos-mediated chemotherapy and Mn²⁺-catalyzed chemodynamic therapy, respectively, thereby leading to significant dendritic cell maturation due to the role of Mn²⁺ 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, Mn²⁺-mediated STING activation, and antibody-mediated immune checkpoint blockade. With the Mn²⁺-endowed r₁ relaxivity (1.38 mM^-1 s^-1), 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.