POS8-0270
Onium-Based Cationic Polymer–Lipid Nanocomplexes for Enhanced Gene Delivery and Therapeutic Applications
Topic
S8. Frontiers of Functional Polymers in Biology and Medicine
When and Where
Sep 30, 2026
08:30 - 09:30
Room 301 (Grand Ballroom)
Session Chairs
Heesuk KIM
Jinhye BAE
Presenter(s)
Dongki Lee (Department of Pharmacy, The Catholic University of Korea, Bucheon, Gyeonggi-do 14662, Korea)
Co-Author(s)
Abstract
Polymer–lipid nanocomplexes (PLNCs) have become promising nonviral gene delivery systems. Although ionizable lipid-based lipid nanoparticles (LNPs) have advanced nucleic acid delivery, their performance is still limited by intracellular trafficking, endosomal escape, and cytotoxicity. Here, we developed PLNCs by replacing ionizable lipids with biodegradable cationic polymers to improve gene transfer. PLNCs were formulated with varying ratios of cationic polymers and helper lipids (DMG-PEG2000, DSPC, and cholesterol) to optimize encapsulation efficiency and physical properties. Biodegradable cationic polymers (TPCL, CPCL, and BPCL) were synthesized by attaching quaternary onium groups to a polymer backbone, enabling plasmid DNA (pDNA) binding with low cytotoxicity. PLNCs exhibited a uniform particle size distribution of 50–200 nm and adjustable surface charges based on zeta potential measurements. They achieved up to 16.6 times higher gene transfection efficiency than LNPs in HEK293 cells. Additionally, therapeutic efficacy was assessed by delivering PTEN pDNA in B16F10 melanoma models, both in vitro and in vivo. Blank PLNCs caused minimal cytotoxicity, with less than 20% cell death, while PTEN pDNA-loaded PLNCs (pPTEN@PLNCs) significantly reduced cancer cell viability, causing up to 80% cell death. Compared to pPTEN@LNPs, pPTEN@PLNCs demonstrated stronger tumor growth inhibition in B16F10 melanoma-bearing mice. The superior gene-delivery ability of PLNCs was attributed to enhanced intracellular trafficking, endosomal escape, and lamellar structural organization. PLNCs with improved endosomal escape facilitated cellular and nuclear delivery of pDNA, likely increasing gene availability. Cryo-TEM confirmed lamellar nanostructures within PLNCs, suggesting that the organized polymer–lipid structure supported stable nucleic acid complexation and intracellular processing. Overall, these features explain the improved transfection efficiency of PLNCs.
