Metal-phenolic network-based polymeric nanocarriers facilitating antibody cytoplasmic delivery and anti-tumor effects to orthotopic breast tumors

Intracellular delivery of antibodies holds great promise for targeting cytosolic antigens involved in various diseases, particularly cancer because many key signal-inducing antigens are localized intracellularly. However, the clinical application of intracellular antibodies is hindered by their poor cellular uptake and inefficient endosomal escape owing to their large molecular weight, hydrophilicity, and overall negative charge. To address these challenges, we developed a metal-phenolic network (MPN)-based polymeric nanocarrier for cytosolic antibody delivery. This carrier was composed of a polyphenol-conjugated polymer and metal ions. Upon simple mixing with antibodies, polyphenol-conjugated polymers and metal ions form polymeric MPN complex-encapsulating antibodies with a core-shell structure. The complex, with a diameter of approximately 30 nm and a relatively neutral charge, demonstrated excellent pharmacokinetics and tumor accumulation following intravenous administration. Within tumor cells, the polymeric MPN complex facilitated endosomal escape through a buffering effect triggered by coordination bond dissociation of MPN in the acidic endosomal environment; simultaneously, the antibodies were released from the polymeric MPN complex, leading to binding to the antigen in the cytoplasm. The polymeric MPN complex enhanced the therapeutic effect of cytoplasmic antigen-binding antibodies against orthotopic breast tumors in mice. This study demonstrated the potential of MPN-based polymeric nanocarriers without cationic molecules as a platform for intracellular antibody delivery, enabling systemic administration and cytosolic release in tumors, thus expanding the therapeutic landscape of antibody-based treatments.