Stimuli-Responsive Polyethylenimine Derivatives as Carriers for siRNA Delivery: Current Solutions and Future...

RNA therapeutics, particularly small interfering RNA, hold great promise for precise gene silencing but still face major challenges related to instability, inefficient delivery, and off-target effects. Polyethylenimine (PEI), a versatile polycation, exhibits strong nucleic acid binding capacity, efficient endosomal escape, and high structural adaptability, making it one of the most promising nonviral delivery platforms. This review summarizes recent advances in stimuli-responsive PEI-based systems, classified according to endogenous triggers such as pH gradients, reactive oxygen species, enzymatic activity, and ATP, as well as exogenous stimuli such as light, temperature, and magnetic fields. Reported strategies include chemical modification, polymer grafting, hybridization with inorganic nanomaterials, and fluorination to enhance specificity, transfection efficiency, and biocompatibility while reducing cytotoxicity. Dual- and multistimuli-responsive designs further enable spatiotemporally controlled release, thereby improving therapeutic efficacy both in vitro and in vivo. Emerging evidence indicates that PEI derivatives represent adaptable, scalable, and clinically relevant platforms for next-generation RNA delivery.