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Development of safe and efficient short interfering RNA (siRNA) delivery system is a current critical challenge in drug delivery field.Cationic lipids are one of the most common nonviral vectors for siRNA delivery, which can efficiently assemble with siRNA to form complexes and have enhanced uptake by cancer cells as well as favourable effects of gene silencing.Nevertheless, complexes which have a cationic surface charge may produce problems associated with toxicity, immune or inflammatory responses, and serum instability.In order to solve these problems, we designed a pH-sensitive siRNA delivery system through modification of cationic liposomes/siRNA complexes (L-TGL+TGLN3/siRNA) with anionic molecule via "click chemistry", which was so facile and reliable as to ensure efficient and harmless modification of the complexes.Our results showed that this pH-sensitive charge-reversal complexes (PCRC) had a negative charge at pH 7.4 and positive charge in tumor acidic environment (pH 6.5).The PCRC were internalized through clathrin-mediated endocytosis and macropinocytosis, followed by successful endosomal escape.The PCRC carrying survivin-specific siRNA (cpusiRNA2) remarkably and specifically down-regulated expression of the survivin and induced BEL-7402 cells apoptosis in vitro.This delivery system with response to acidic environment of tumor tissues would have remarkable potential in cancer therapy.