Development of a Lysine-Based Poly(ester amide) Library with High Biosafety and a Finely Tunable Structure for Spatiotemporal-Controlled Protein Delivery

With the fast growth of protein therapeutics, efficient, precise, and universal delivery platforms are highly required. However, very few reports have discussed the progress of precisely spatiotemporal-controlled protein delivery. Therefore, a mini library of well-designed amino acid-based poly(ester amide)s derived from lysine (Lys-aaPEAs) has been developed. Lys-aaPEAs can interact with and encapsulate proteins into nanocomplexes via electrostatic interactions. The chemical structure of Lys-aaPEAs can be finely tuned by changing the type and molar ratio of the monomers. Studies of structure–function relationships reveal that the carbon chain length of diacid/diol segments, hydrophilicity, and electrical properties affect the polymer–protein interaction, cell–material interaction, and, therefore, the outcome of protein delivery. By modulating the structures of Lys-aaPEAs, the delivery systems could present customized physiochemical and biological properties and perform time- and space-specific protein release and delivery without causing any systematic toxicity. The screened systems exhibited prolonged hypoglycemic activity and superior biosafety in vivo, using insulin as a model protein and a mouse model bearing type 1 diabetes mellitus (T1DM). This work establishes a novel lysine-based polymer platform for spatiotemporal-controlled protein delivery and offers a paradigm of precise structure–function controllability for designing the next generation of polymers.