Poly-γ-glutamic acid-based GGT-targeting and surface camouflage strategy for improving cervical cancer gene therapy

Polycation-based delivery presents a major method for non-viral gene therapy. However, the disadvantages of cationic vectors are their tendencies to be captured and eliminated by the reticuloendothelial system due to their excessive positive charges and nonspecific interaction with normal cells that leads to adverse effects. PEGylation was applied to solve these major problems. Yet, PEG chains can severely compromise cellular uptake and yield unsatisfying efficiency resulting in a so-called PEG dilemma. We developed a gamma-PGA-based GGT-targeting and surface camouflage strategy by constructing a ternary complex system via a layer-by-layer self-assembly method. The biodegradable polyanion gamma-PGA could protect the PEI/pDNA complexes from interaction with the body fluid components; however, in endosome, the polyanion facilitated the intracellular release of PEI/pDNA. The gamma-PGA/PEI/pDNA nanoparticles possessed a markedly improved serum-tolerant capability. More importantly, gamma-PGA interacts with the tumor-associated g-glutamyl transpeptidase (GGT) that can mediate endocytosis of the nanoparticles. With pTRAIL as the therapeutic gene, the gamma-PGA/PEI/pTRAIL nanoparticles effectively inhibited tumor cell proliferation by inducing cell apoptosis and arresting cell cycles. The in vivo results displayed effective suppression of tumor growth, and high treatment efficacy in the mice bearing cervical tumor. The gamma-PGA-based GGT-targeting and surface camouflage strategy is a potential method for improved gene delivery and cancer therapy.