Aptamers can bind a wide range of biomedically relevant proteins with affinities and specificities that have therapeutic utility. Although aptamers are susceptible to nuclease-mediated degradation and cannot easily cross biological barriers, specific aptamer modification can feasibly solve these problems. To address these obstacles, Lau et al. developed a general strategy for generating natural packaging and transport vehicles for targeting agents, such as aptamers and their small-molecule ligands, by using virus-like particles (VLPs) assembled from the recombinant expression of the bacteriophage Qβ coat protein. Since RNA and DNA molecules are susceptible to nuclease-mediated degradation, it is important that Qβ VLPs protect their encapsulated aptamers from nuclease-mediated degradation and enhance their permeability. Moreover, if self-assembled using natural proteins, VLPs can guarantee the biocompatibility and biodegradability of modified aptamers in therapeutic applications. Therefore, this Perspective explores the outlook for such aptamer modification strategies for nanodrug preparation and delivery applications and the challenges that lie ahead.