Next generation protein-corrole bio-assemblies provide effective tumoricidal treatment in a metastatic triple-negative breast cancer model

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. SignificanceTriple-negative breast cancer (TNBC) is an aggressive disease with high rates of metastasis and mortality, largely because it lacks molecular targets for precision therapy. As a result, patients rely primarily on chemotherapy, which causes systemic toxicity and frequently fails to control metastatic spread. Here, we introduce a targeted therapeutic strategy in which a bioengineered protein selectively recognizes a receptor highly expressed in metastatic TNBC and delivers a potent cytotoxic payload directly into tumor cells. In mouse models, this approach produced robust tumor regression, markedly reduced lung metastases, extended survival, and showed minimal off-target toxicity. These findings establish a versatile platform for targeted treatment of TNBC and highlight a strategy that may be broadly applicable to other HER3-expressing cancers.