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Adenovirus (Ad)-based cancer therapies have shown much promise. However, until now, Ad has only been delivered directly to primary tumors because the therapeutic efficacy of systemic delivery is limited by the immune response of the host, short blood circulation times, and non-specific liver uptake of Ad. In order to circumvent the issues regarding systemic delivery and to increase the safety and efficacy of Ad therapies, the surface of oncolytic Ad was coated with cationic polymer chitosan via ionic crosslinking (Ad/chitosan), after which polyethylene glycol (PEG) and/or folic acid (FA) was chemically conjugated onto the surface of Ad/chitosan, generating Ad/chitosan–FA, Ad/chitosan–PEG, and Ad/chitosan–PEG–FA nanocomplex. The FA-coordinated Ad nanocomplexes (Ad/chitosan–FA & Ad/chitosan–PEG–FA) elicited folate receptor (FR)-selective cancer cell killing efficacy. In vivo administration of Ad/chitosan–PEG or Ad/chitosan–PEG–FA into mice demonstrated that PEGylation greatly increased blood circulation time, resulting in 9.0-fold and 48.9-fold increases at 24 h after injection compared with naked Ad, respectively. In addition, generation of Ad-specific neutralizing antibodies in mice treated with Ad/chitosan–PEG–FA was markedly decreased by 75.3% compared with naked Ad. The quantitative polymerase chain reaction assay results showed a 285.0-fold increase in tumor tissues and a 378-fold reduction of Ad/chitosan–PEG–FA in liver tissues compared with naked Ad. Bioluminescence imaging study further supported the enhanced tumor-to-liver ratio of Ad/chitosan–PEG–FA. Consequently, systemic delivery of Ad/chitosan–PEG–FA significantly inhibited the growth of FR-positive tumor, decreasing 52.8% compared to the naked Ad-treated group. Importantly, PEGylated oncolytic Ad nanocomplexes showed no elevation of both alanine transaminase and aspartate transaminase levels, demonstrating that systemically delivered Ad-related hepatic damage can be completely eliminated with PEG conjugation. In sum, these results demonstrate that conjugation of chitosan–PEG–FA to oncolytic Ad significantly improves antitumor efficacy and safety profiles, suggesting that Ad/chitosan–PEG–FA has potential as a therapeutic agent to target FR-positive cancer via systemic administration.