Abstract
Assemblies that combine chemotherapeutics with tumor-targeting proteins are promising agents for treating resistant cancers but require full biochemical characterization before therapeutic deployment. We developed and optimized a HER3-targeting capsomere, HPK2.0, which forms stable nanoscale assemblies with cytotoxic corroles via electrostatic neutralization and shape complementarity. These nanocomplexes exhibit durable serum stability, HER3-dependent tumor invasion, and efficient endosomal escape, resulting in potent and selective cytotoxicity in triple-negative breast cancer (TNBC) cells. In an orthotopic metastatic TNBC model, systemic treatment with HPK2.0-corrole assemblies achieved 67-83% tumor regression, near-complete suppression of spontaneous lung metastasis, and a ~2-fold improvement in survival relative to mock treatment, with minimal off-target toxicity. By integrating tumor specificity with therapeutic potency, this next-generation protein-corrole platform establishes a clinically scalable strategy for treating metastatic HER3-positive TNBC.