LAUSR

ABSTRACT Introduction Despite the great therapeutic potential of gene therapy for treating critical diseases, the clinical application is limited by lack of safe and effective gene delivery vectors. Nonviral gene vectors have attracted tremendous attention due to the favorable loading capacity and facile manufacture. Among them, polyethylenimine-based gene vectors (PEIs) hold great promise for highly efficient gene delivery. Areas covered In this review, we outline the multiple biological barriers associated with gene delivery process and point out several challenges exist in the clinical usage of PEIs. We then provide an overview of the most impressive progresses made to overcome such challenges in recent years, including modifications of PEIs (i.e. to enhance biocompatibility, specific targeting effect, and buffering capacity) and stimuli-responsive strategies (i.e. endogenous and exogenous stimuli) for safe and efficient gene delivery. Expert opinion Rational modification of PEIs with diverse functionalized segments or the development of stimuli-responsive PEIs is an appealing strategy to meet some requirements involved in gene delivery. Nevertheless, further optimization by combining the two strategies is needed for the maximized transfection efficiency and minimized side effects, shedding new light on the development of nonviral gene delivery for clinical application.