Amphiphilic Phenyl Carbamoyl Guanidine-Modified ε-Poly-l-Lysine Enables Efficient Intracellular Antibody Delivery

Peptide-based intracellular delivery carriers are known for their biocompatibility, tunability, and ability to transport various macromolecular cargos. Among these, a naturally derived epsilon-poly-l-lysine (εPL) has been studied for nucleic acid complexation and delivery. However, εPL lacks the amphiphilic properties necessary to stably complex proteins, interact with cellular membranes, or facilitate endolysosomal escape. Hydrophobic derivatives of εPL are rare, and their application in intracellular protein delivery has not yet been demonstrated. Here, we report amphiphilic phenyl carbamoyl guanidine (PhCG)-modified εPLs that enable the intracellular delivery of necrosis-inducing antibodies, leading to a dose-dependent reduction in cellular viability through caspase-independent, membrane-compromised cell death. Varying the degree of PhCG substitution identified an optimal ∼25-50% modification for effective antibody delivery. Binding assays indicate that synergistic noncovalent interactions─strengthened by local hydrophobicity, hydrogen bonding, and electrostatic forces─drive complexation and delivery. These findings establish PhCG-modified εPL as an efficient, serum-tolerant carrier for intracellular antibody delivery.