Nanomedical applications of biodegradable poly(DL-lactide-co-glycolide) (PLGA) nanoparticles (NPs) developed are discussed in this review. A surface-functionalized PLGA NP platform for drug delivery was established to encapsulate a number of macromolecular drugs such as peptides and nucleic acids as well as low-molecular-weight drugs by the emulsion solvent diffusion method. The interaction of PLGA NPs with cells and tissues could be controlled by changing the surface properties of NPs, suggesting their potential utility for the intracellular drug delivery of nucleic acid-based drugs. Furthermore, orally administered NF-κB decoy oligonucleotide-loaded CS-PLGA NPs are also useful in treating experimental colitis. These approaches using surface-modified PLGA NPs could be able to open new possibilities for nucleic acid-based drug delivery via noninvasive administration method.