Oligosaccharide and alkyl chain-modified polyethyleneimines for efficient siRNA delivery

Cationic polymers like polyethyleneimine (PEI) are widely used for siRNA delivery, but their high positive charge density often compromises biocompatibility and in vivo stability. Balancing effective siRNA binding with reduced cytotoxicity remains a critical challenge for clinical translation. Here, we report a dual-functional modification strategy for PEI using oligosaccharides (maltose/maltotriose) and hydrophobic n-octanal to mitigate excessive cationic charge, enhance stability, and improve delivery efficiency. By synthesizing oligosaccharide-modified PEIs (OM-PEIs) and hydrophobically modified OM-PEIs (H-OM-PEIs), we identified PEI_25k-based derivatives (HC4 and HD4) as top performers, achieving complete siRNA loading at a low polymer:siRNA mass ratio (4:1, wt/wt) while exhibiting 50 % reduced protein adsorption and superior siRNA protection compared to unmodified PEI_25k. The hydrophobic modification enabled H-OM-PEIs to form compact nanoparticles with enhanced cellular uptake, leading to robust luciferase silencing in HeLa cells (2.5-fold improvement over PEI_25k). Notably, in vivo studies revealed significant liver accumulation alongside detectable tumor delivery. This study demonstrated that combining oligosaccharide and alkyl modifications of PEI can reduce surface charge and protein adsorption while maintain high siRNA delivery efficiency, thereby mitigating the inherent toxicity of PEI and enhancing nanoparticle stability, which contributes to the advancement of PEI-based delivery systems in practical applications.