mRNA nanomedicine reprograms the cell cycle to increase the effectiveness of targeted therapy for HER2-low breast cancers.

Over 70 % of breast cancer patients present with tumors exhibiting low or undetectable HER2 expression, making them largely unresponsive to current HER2-targeted therapies. To address this, we developed an innovative lipid nanoparticle (LNP)-based mRNA nanomedicine that reprograms tumor cell cycle by restoring expression of both HER2 and p53 genes, two key regulators of tumor progression and treatment resistance. This combination strategy induces synergistic tumor cell death, particularly in p53-deficient, HER2-low/negative breast cancers. Importantly, this approach sensitized previously unresponsive tumors to trastuzumab, a HER2-targeted antibody. In vivo studies using HER2-low patient-derived xenograft (PDX) and HER2-negative cell-derived xenograft (CDX) models further demonstrated robust tumor regression. This novel mRNA nanomedicine represents a transformative therapeutic strategy, offering a promising solution for patients with HER2-low cancers who currently have limited treatment options.