Lipid nanoparticles (LNPs) are one of the promising technologies for the in vivo delivery of short interfering RNA (siRNA). Modifying LNPs with polyethyleneglycol (PEG) is widely used to inhibit non-specific interactions with serum components in the blood stream, and is a useful strategy for maximizing the efficiency of active targeting. However, it is a widely accepted fact that PEGylation of the LNP surface strongly inhibits fusion between LNPs and endosomal membranes, resulting in poor cytosolic siRNA delivery, a process that is referred to as the ‘PEG-dilemma’. In the present study, in an attempt to overcome this problem, siRNA-loaded LNPs were modified with PEG through maleic anhydride, a pH-labile linkage. The in vitro, suppression of cationic charge, stealth function at physiological pH up to 1 h and the rapid desorption of PEG and restoration of fusogenic activity under slightly acidic conditions (within only 2 min) were achieved by PEG modification of the LNPs through maleic anhydride. In vivo, PEG modification through maleic anhydride resulted in a dramatic improvement in the targeting capability of the active targeting of ligand (N-acetyl-d-galactosamine)-modified LNPs to hepatocytes, with an approximately 14-fold increase in gene silencing activity in factor 7 model mice. Taken together, the maleic anhydride-mediated pH-labile PEGylation of the active targeting LNPs is a useful strategy for achieving the specific and efficient delivery of siRNAs in vivo.