Rationally Designed PBAE Nanoparticles Enable Precision of Delivery Therapeutic to Pulmonary Endothelial Cells

Introduction and Background: Endothelial cell dysfunction is a critical factor in acute and chronic pulmonary diseases, yet current gene delivery systems fail to achieve efficient and organ-specific targeting. Traditional nanoparticle systems face significant limitations: inhaled nanoparticles struggle to penetrate biological barriers, while systemically administered nanoparticles lack organ specificity. We report a breakthrough in nanoparticle design that addresses these critical challenges, offering a novel solution for precision gene therapy targeting pulmonary endothelial cells.
Methods/Experimental Approach: We systematically optimized Poly (β-amino ester) (PBAE nanoparticles by tuning their chemical structures with varying backbone hydrophobicity, capping agents (PEG, PEI), and fluorination. Additionally, we identified key assembly parameters that enhance transfection efficiency. In Vivo Imaging System (IVIS) confirmed the nanoparticle transfection efficiency and organ specificity in vivo.
Results: Our breakthrough findings demonstrate that rational design of PBAE nanoparticles, incorporating fluorinated molecules and optimizing polymer hydrophobicity can dramatically enhance nanoparticle stability, transfection efficiency, and lung specificity. Notably, by fine-tuning nanoparticle-to-nucleic acid ratios achieved highly efficient delivery of non-integrating DNA/plasmid, stabilized mRNA, and hydrophobic small molecular compounds to pulmonary endothelial cells through intravenous route while minimizing off-target accumulation in organs such as the liver and spleen. This represents a major advancement in overcoming the limitations of current nanoparticle delivery systems.
Conclusions: This work introduces a rational design for nanoparticle-based therapeutics, demonstrating that tailored chemical and assembly strategies can overcome delivery barriers. These findings have the potential to revolutionize the treatment of endothelial cell dysfunction in pulmonary diseases, paving the way for clinical translation of targeted nanoparticle-based therapies.