Multicheckpoint Cellular Targeting of siRNAs Using Antibody-Directed Lipid-Polymer Hybrid Nanoparticles.

Despite advancements in tissue-specific gene therapy, current technologies struggle to target organs beyond the liver, spleen, and lungs. Passive approaches such as selective organ targeting (SORT) lipids show potential but require time-intensive optimization. Active targeting, exemplified by antibody-drug conjugates (ADCs), offers a modular and effective alternative. Building on this, we developed antibody-functionalized hybrid lipid-polymer nanoparticles for siRNA delivery, targeting cancer-overexpressed receptors such as EGFR and TROP2, prevalent in aggressive cancers like triple-negative breast cancer (TNBC). In addition, to enhance therapeutic safety and efficacy, we integrated multi-siRNA delivery into a multicheckpoint targeting strategy, minimizing reliance on single antigens and reducing off-target risks. Using TNBC cells as a model, this platform demonstrates potential for developing a robust and safe therapeutic approach. In this article, we present our findings that lay the foundation for developing a multicheckpoint strategy to enhance target selectivity in nanomedicine.