Arginine-based poly(ester amide) nanoparticle platform: From structure-property relationship to nucleic acid delivery.

Many different types of polycations have been vigorously studied for nucleic acid delivery, but a systematical investigation of the structure-property relationships of polycations for nucleic acid delivery is still lacking. In this study, a new library of biodegradable and biocompatible arginine-based poly(ester amide) (Arg-PEA) biomaterials was designed and synthesized with a tunable structure for such a comprehensive structure-property research. Nanoparticle (NP) complexes were formed through the electrostatic interactions between the polycationic Arg-PEAs and anionic nucleic acids. The following structure effects of the Arg-PEAs on the transfection efficiency of nucleic acids were investigated: 1) the linker/spacer length (length effect and odd-even effect); 2) salt type of arginine; 3) the side chain; 4) chain stiffness; 5) molecular weight (MW). The data obtained revealed that a slight change in the Arg-PEA structure could finely tune its physicochemical property such as hydrophobicity, and this could subsequently affect the nanoparticle size and zeta potential, which, in turn, regulate the transfection efficiency and silencing outcomes. A further study of the Arg-PEA/CpG oligodeoxynucleotide NP complexes indicated that the polymer structure could precisily regulate the immune response of CpG, thus providing a new potential nano-immunotherapy strategy. The in vitro data have further confirmed that the Arg-PEA NPs showed a satisfactory delivery performance for a variety of nucleic acids. Therefore, the data from the current study provide comprehensive information about the Arg-PEA structure-transfection property relationship; the tunable property of the library of Arg-PEA biomaterials can be one of the promising candidates for nucleic acid delivery and other biomedical applications. STATEMENT OF SIGNIFICANCE: Polycations have being intensive utilized for nucleic acid delivery. However, there has not been elucidated about the relationship between polycation's structure and the physicochemical properties/biological function. In this timely report, an arginine based poly(ester amide) (Arg-PEA) library was prepared with finely tunable structure to systematically investigate the structure-property relationships of polycations for nucleic acid delivery. The results revealed that slight change of Arg-PEA structure could finely tune the physicochemical property (such as hydrophobicity), which subsequently affect the size and zeta potential of Arg-PEA/nucleic acid nanoparticles(NPs), and finally regulate the resulting transfection or silencing outcomes. Further study of Arg-PEA/CpG NPs indicated that the polymer structure could precisely regulate immuno response of CpG, providing new potential nano-immunotherapy strategy. In vitro evaluations confirmed that the NPs showed satisfied delivery performance for a variety types of nucleic acids. Therefore, these studies provide comprehensive information of Arg-PEA structure-property relationship, and the tunable properties of Arg-PEAs make them promising candidates for nucleic acid delivery and other biomedical applications. Overall, we have shown enough significance and novelty in terms of nucleic acid delivery, biomaterials, pharmaceutical science and nanomedicine.