TABLE II.

Important considerations for the design of DNA-based nanodevices that are envisioned to perform a function in a complex biological setting.

Problem	Solution	Associated risk
Off-target biodistribution (accumulation in organs, kidney filtration)	Increasing the molecular size by complex formation with other molecules; altering the object size, surface charge, or shape	Cellular uptake will be more difficult
Off-target action	Conjugation with target molecules (aptamer, antibody, peptide, ligand, protein), choosing highly specific gene targets	Local overdose, lower efficiency of drugs due to conjugation
Toxicity	Using biodegradable vectors	Premature release from the DNA construct before it has reached its target
Immunogenic reactions	Pretreatment using corticosteroids and anti-allergy medications, 2′-O-methyl base modifications	Overstimulation of the immune system
Quick degradation in a biological environment (e.g., by serum RNase), endosomal degradation	Altering the oligonucleotide chemistry, (e.g., methylation, peptide conjugation, phosphorothioate modification), protective coatings (oligolysine, PEG, polypeptides), using endosomolytic agents (e.g., melittin), carriers (polymer or lipid based)	Cytotoxic effects, reduced activity (e.g., for siRNA)
Low intracellular uptake	Using cationic carrier particles, PEGylation, transfection vectors, electroporation, lipid conjugation	Aggregation with serum proteins, accumulation of transport material in the cell