Abstract
Breast cancer is the most prevalent malignancy worldwide, with approximately 50% of HER2-positive advanced breast cancer patients eventually developing brain metastases, significantly reducing survival. Current HER2-targeted therapies, such as trastuzumab, exhibit limited efficacy in patients with brain metastases due to poor blood-brain barrier penetration and drug resistance. This study aimed to develop a novel strategy for treating HER2-positive breast cancer brain metastases to improve overall survival. We engineered nanoparticles encapsulating circular RNA encoding the chemokine CXCL9 and an anti-PD-1 scFv, designed to target HER2-positive brain metastases. Our results demonstrate that these nanoparticles significantly enhance anti-tumor activity both in vitro and in vivo without exhibiting significant systemic toxicity. This approach improves the local tumor immune microenvironment while inducing lower systemic toxicity. In conclusion, we have established a platform of membrane-encapsulated circular RNA nanoparticles capable of targeting brain tumor lesions, showing potential for application in various brain disorders, including metastatic brain tumors. This novel approach offers a promising strategy for addressing the urgent need for effective treatments for HER2-positive breast cancer brain metastases.