We report a new synthetic strategy that allows for the facile synthesis of acid-degradable poly(ethylene glycol) (PEG) with tunable acid sensitivity at physiologically relevant pH. This approach relies on the step-growth of telechelic OEG/PEG diamine and bis(maleic anhydride)s with the acid-cleavable maleamic acid derivatives formed in situ during the polymerization. These polymers are stable and negatively charged in neutral and basic aqueous solution, but in physiologically acidic media, they can be degraded selectively and completely into metabolizable bis(maleic acid)s and OEG/PEG diamines. The polymers derived from the short OEG diamine have been used as acid-responsive polyanions to coat the positively charged DNA/PEI polyplex, thus enhancing the stability of the coated polyplex against bovine serum albumin at pH 7.4. Upon exposure to a weakly acidic medium, the positively charged DNA/PEI polyplex can be quickly regenerated.