A nonionic and water-soluble polyphosphoester, poly(2-hydroxyethyl propylene phosphate) (PPE3), wassynthesized by chlorination of poly(4-methyl-2-oxo-2-hydro-1,3,2-dioxaphospholane), followed by esterificationwith 2-benzyloxyethanol and deprotection of the hydroxyl group by catalytic hydrogenation in thepresence of Pd-C. PPE3 degraded rapidly in PBS 7.4 at 37℃. The cytotoxicity and tissue compatibilityassays suggested good biocompatibility of PPE3 in vitro and in vivo. The expression of pVR1255 Lucplasmid in mouse muscle after intramuscular (i.m.) injection of DNA formulated with PPE3 solution insaline was enhanced up to 4-fold compared with that of naked DNA. These results suggest the potential ofthis polyphosphoester for naked DNA-based gene therapy. The advantages of this polymer design includethe biodegradability of the polyphosphoester and its structural versatility, which allows the fine-tuning ofthe physicochemical properties to optimize the enhancement of gene expression in muscle.