For nanoparticles to become safely used for drug delivery or gene therapy, it will be essential to demonstrate that they affect the cells they enter via the intended effect of the cargo they deliver—not through unexpected interference with cellular function or gene expression, which is much more likely to be harmful than beneficial. Now researchers led by 2002 Foresight Institute Feynman Prize in Nanotechnology-Experimental winner Chad Mirkin have demonstrated that nucleic acids loosely bound to gold nanoparticles have profound, unanticipated effects on cellular gene expression, while nanoparticles carrying covalently bound nucleic acids produce no unintended effects on cellular gene expression. Understanding How Cells Respond to Nanoparticles:
Gold nanoparticles are showing real promise as vehicles for efficiently delivering therapeutic nucleic acids, such as disease-fighting genes and small interfering RNA (siRNA) molecules, to tumors. Now, a team of investigators from Northwestern University has shown that the safety of gold nanoparticle-nucleic acid formulations depends significantly on how the nucleic acids and nanoparticles are linked to one another, a finding with important implications for those researchers developing such constructs.
…To measure how cancer cells respond when they take up nanoparticles, Dr. Mirkin and his colleagues used a technique known as genome-wide expression profiling, which measures relative changes in global gene expression. The investigators added different types of nanoparticles to cancer cells growing in culture dishes and then obtained whole genome expression profiles for the cells. In all the experiments, the researchers attached non-targeting nucleic acids attached to the nanoparticles in order to minimize gene changes that might be triggered through a therapeutic effect relating to a specific, designed interaction between the nucleic acid and a targeted gene.
The results of these comparison studies showed that the surface properties of the nanoparticles had a profound impact on how a given nanoparticle impacts gene expression within a cell. The researchers observed the most surprising and noteworthy difference when they compared two nanoparticles that differed only in the manner in which the nucleic acids were attached to the nanoparticle surface. Nanoparticles loosely linked to the nucleic acids triggered large-scale changes in gene expression, while in contrast, nanoparticles linked tightly to nucleic acids through a covalent chemical bond had virtually no effect on gene expression. These findings, the researchers noted, show how important it is to fully characterize nanoparticles not only in terms of the shape and size, but also with respect to their surface properties.
The abstract of the research paper from the journal’s website:
Nanoparticles are finding utility in myriad biotechnological applications, including gene regulation, intracellular imaging, and medical diagnostics. Thus, evaluating the biocompatibility of these nanomaterials is imperative. Here we use genome-wide expression profiling to study the biological response of HeLa cells to gold nanoparticles functionalized with nucleic acids. Our study finds that the biological response to gold nanoparticles stabilized by weakly bound surface ligands is significant (cells recognize and react to the presence of the particles), yet when these same nanoparticles are stably functionalized with covalently attached nucleic acids, the cell shows no measurable response. This finding is important for researchers studying and using nanomaterials in biological settings, as it demonstrates how slight changes in surface chemistry and particle stability can lead to significant differences in cellular responses.
Among the applications of nanoparticles currently being developed, some of the most exciting involve producing very specific, targeted changes in cellular gene expression. Eliminating unintended effects must be a fundamental design criterion.