pH-Responsive Polymers as Gene Carriers In-Kyu Park, Kaushik Singha, Rohidas B. Arote, Yun-Jaie Choi, Won Jong Kim,* Chong-Su Cho* Introduction Nonviral-vector-mediated gene delivery is comprised of several key steps namely, the packaging of genes, admin- istration, transportation to specific target site, internaliza- tion, endolysosomal escape, efficient unpackaging, and nuclear transport. [1–3] The journey toward efficient gene delivery encounters several impediments associated with each of these steps. To circumvent all these hurdles, a tremendous amount of research activities are in progress. The negatively charged DNA undergoes compaction with a cationic polymer through strong electrostatic interactions, thereby forming nanosized polyplexes. [4–6] However, upon intravenous administration, these cationic polyplexes interact strongly with various negatively charged blood components to result in a rapid clearance of the polyplexes out of the blood stream and concomitant poor transfection in the target site. [6–8] The shielding of these cationic polyplexes by neutral or slightly negatively charged polymers could provide the means to overcome the serum instability issue. [9–12] Ironically, the shielding itself imposes another obstacle by reducing the compromised cellular uptake and endosomal escape, and thereby leads to Review K. Singha, W. J. Kim Department of Chemistry, Pohang University of Science and Technology (POSTECH), Pohang, Kyungbuk, 790-784, Korea Fax: þ82-54-279-3399; E-mail: wjkim@postech.ac.kr R. B. Arote, Y.-J. Choi, C.-S. Cho Department of Agricultural Biotechnology, Seoul National University, Seoul 151-921, Republic of Korea Fax: þ82-54-279-3399; E-mail: chocs@plaza.snu.ac.kr I.-K. Park Department of Biomedical Sciences, Chonnam National University Medical School, Chonnam National University, Gwangju 501-746, Korea R. B. Arote, C.-S. Cho Research Institute for Agriculture and Life Sciences, Seoul National University, Seoul 151-921, Republic of Korea Despite the immense potential of non-viral delivery system in gene therapy its application has been impaired greatly by various impediments having contrasting traits. Therefore it is an absolute necessity to develop some non-viral vectors which are endowed with special characteristics to act differently in intracellular as well as extracellular compartments to surmount these inter-conflicting hurdles. Such smart polymers should serve some specific purposes by adjusting their structural or functional traits under the influence of stimuli such as temperature, light, salt concentration or pH. Among all these stimuli-responsive polymers pH-responsive polymers have attracted major attention and great impetus has been directed towards utilizing the subtle yet significant change in pH value within the cellular compartments. This review is intended to provide a comprehen- sive account of the development of pH-responsive polymeric vectors based on their structural fea- tures and consequent functional attributes to achieve efficient transfection. The underlying modes of actions relating to structure and differ- ential pH environment have also been discussed in this review. 1122 Macromol. Rapid Commun. 2010, 31, 1122–1133 ß 2010 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim DOI: 10.1002/marc.200900867