Her2-targeted p53 mRNA-LNP platform: A novel strategy for overcoming radioresistance in p53-deficient ovarian cancer

Extending our previous findings on Her2-targeted lipid nanoparticles (LNPs) for p53 mRNA delivery, this study evaluates this platform's potential as a radiosensitizer to counteract p53-deficiency-mediated radioresistance. p53 or firefly luciferase (Fluc, non-therapeutic control) mRNA was encapsulated in LNPs functionalized with Her2-specific antibodies (p53@HER-LNP or Fluc@HER-LNP). Utilizing p53-null, Her2-overexpressing SKOV3 cells and xenografts, we assessed synergistic efficacy of radiotherapy (RT) and the targeted mRNA platform. For in vivo validation, 0.5 mg/kg of LNPs were administered intravenously one day prior to and one day after local tumor irradiation (4 or 8 Gy). The p53@HER-LNPs effectively restored p53 expression, eliciting robust apoptosis. When integrated with RT, this targeted nanotherapeutic significantly potentiated DNA damage-induced cytotoxicity and attenuated clonogenic survival compared to RT alone or Fluc-loaded controls. Notably, in vitro scheduling analysis identified that p53 mRNA administration subsequent to RT (post-RT) exerted a more pronounced synergistic effect than pre-RT treatment. These results were recapitulated in vivo, where the p53@HER-LNP + RT cohort exhibited superior tumor growth inhibition and enhanced radiosensitivity compared to both RT alone and the Fluc@HER-LNP control group. Consequently, targeted p53 restoration via antibody-conjugated LNPs represents a robust strategy for maximizing RT efficacy, offering a rational framework for optimized clinical scheduling in Her2-positive, radioresistant malignancies.