pH-sensitive ternary nanoparticles for nonviral gene delivery

PEGylation, which is reversed after the therapeutic agent reaches the target cell, presents attractive features for drug, protein or gene delivery. Herein, a tumor acidity-responsive PEGylated anionic polymer was synthesized for bioreversible surface shielding of DNA complexes. The pH-sensitive and non-pH-sensitive ternary nanoparticles were respectively fabricated by introducing tumor acidity-responsive PEGylated anionic polymer and its corresponding pH stable analog to the surface of positively charged PEI25K/DNA complexes via electrostatic interaction. We show clear evidence that introducing the PEGylated anionic polymer to the surface of a nanoparticle markedly reduces its nonspecific interactions with protein. We further demonstrate that the pH-sensitive ternary nanoparticle versus non-pH-sensitive analog is capable of reversing its surface charge from neutral to positive at the slightly acidic tumor extracellular microenvironment to facilitate the delivery of DNA. Such delivery system with the ability to deshield the PEG layer at the target tissues has remarkable potential in gene delivery.