Inefficient transfection of biocompatible low-molecular-weight (LMW) polycations, such as 1.8k polyethylenimine (PEI), is a major challenge for successful nucleic acid delivery. Current strategies to improve transfection efficiency are bottlenecked by maintaining the balance between efficient gene encapsulation and on-demand cargo release. Here, we developed a new class of Zn(II)-coordinated micelles, which showed tight small interfering RNA (siRNA) binding and pH-switchable release. The dipicolylamine-modified PEI 1.8k (PD) and dopamine-conjugated cholesterol (Chol-Dopa) assemble into coordinative micelles (Zn-PD/Chol-Dopa) via the coordination of 2,2'-dipicolylamine (DPA) and Dopa through Zn(II) as a bridge. The high phosphate-binding affinity of Zn-DPA enhanced the siRNA packaging and the interaction between cholesterol and cell membranes enhanced cellular uptake. Moreover, the coordination effect weakened in the acidic environment of lyso/endosome, triggering the disassembly of micelles and siRNA release. These properties of the micelles resulted in strong siRNA transfection efficiencies in various cell lines. Our strategy of constructing coordinative micelles improves the transfection efficiency of LMW PEI and holds tremendous potential to develop the endogenous responsive gene delivery systems.
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