DNA delivery to cells can be improved by using particulate carriers made from biodegradable polymers such as poly(lactic-glycolic)acid. Modifications to the particle surface can be incorporated to enhance cellular uptake and gene expression. Taking advantage of known receptor/ligand interactions in intestinal and renal epithelial cells, we formulated PLGA particles coated with BSA. The modified particles exhibited a marked increase in uptake by cells expressing the albumin receptor, megalin, and a higher stability following prolonged incubation at physiological and low pH compared to uncoated particles. However, the slower, sustained release of DNA from particles due to incorporation of BSA resulted in significantly lowered gene expression in cells. Adding features to the design of 'smart' particles for DNA delivery, thus, can introduce unfavorable characteristics that reduces treatment efficacy. Our study highlights the importance of considering these factors in engineering polymer drug carriers, and the need to understand better the mechanisms that govern the processing of particles in cells.