Regulation of oligonucleotide adsorption by a thermo and pH dual-responsive copolymer layer

Oligonucleotides hold great promise as therapeutic agents to specifically and selectively inhibit gene expression. In order to achieve better targeting efficiency and treatment efficacy, nanocarriers that are dual-responsive to both temperature and pH are more attractive and suitable due to the fact that certain malignancies can cause a slight increase of local temperature and a minor decrease in extracellular pH around the tumor site at the same time. Here, we systematically study oligonucleotide adsorption on the poly(ethyleneimine)-b-poly(N-isopropylacrylamide) (PEI-b-PNIPAm) copolymer layer grafted on a planar surface and nanoparticles with various radii, where the single effect of temperature or pH alone on oligonucleotide adsorption has been extensively investigated, but the combined effect of temperature and pH is less discussed. The theoretical results show that the surface density of the adsorbed oligonucleotides exhibits thermo and pH dual-responsive behavior, in which temperature and pH exhibit a combined effect on the loading capacity of the oligonucleotides. The underlying molecular mechanism of the dual-responsive behavior is revealed. Besides, the effect of important but coupled parameters in nanocarrier design such as polymer surface coverage and length, salt concentration as well as surface curvature (inverse nanoparticle radius) that may influence the dual-responsive behavior of oligonucleotide adsorption is further discussed, which is of great significance to direct the optimal design of PNIPAm/PEI-based nanocarriers to improve the transfection efficiency by achieving the maximal loading capacity of oligonucleotides at different temperatures and pH values.