Cationic polymers are one of the main non-viral vectors for gene therapy, but their applications arehindered by the toxicity and inef?cient transfection, particularly in the presence of serum or otherbiological ?uids. While rational design based on the current understanding of gene delivery process hasproduced various cationic polymers with improved overall transfection, high-throughput parallel syn-thesis of libraries of cationic polymers seems a more effective strategy to screen out ef?cacious polymers.Herein, we demonstrate a novel platform for parallel synthesis of low cationic charge-density polyestersfor ef?cient gene delivery. Unsaturated polyester poly(alkylene maleate) (PAM) readily underwentMichael-addition reactions with various mercaptamines to produce polyester backbones with pendantamine groups, poly(alkylene maleate mercaptamine)s (PAMAs). Variations of the alkylenes in thebackbone and the mercaptamines on the side chain produced PAMAs with tunable hydrophobicity andDNA-condensation ability, the key parameters dominating transfection ef?ciency of the resulting poly-mer/DNA complexes (polyplexes). A semi-library of such PAMAs was exampled from 7 alkylenes and 18mercaptamines, from which a lead PAMA, G-1, synthesized from poly(1,4-phenylene bis(methylene)maleate) and N,N-dimethylcysteamine, showed remarkable transfection ef?ciency even in the presenceof serum, owing to its ef?cient lysosome-circumventing cell ular uptake. Furthermore, G-1 polyplexesef?ciently delivered the suicide gene pTRAIL to intraperitoneal tumors and elicited effective anticanceractivity.