Chemically modified inorganic nanoparticles (NPs) hold great promise for biomedical applications. In this review, we examine the recent advances in nanotechnology for targeted drug delivery and controlled drug release. The development of an effective drug delivery system requires good understanding of the chemical and physical properties that affect the interaction of nanoparticles with the biological environment. A robust drug carrier should have an appropriate circulation time and should not exert any harmful effect on normal cells. The nanostructures involved must satisfy the requirements of no pre-release of drugs, stability and biocompatibility in vivo, targeted delivery to cancer cells/inflammation area, and on-demand release of drugs. Herein we summarize the surface modifications of nanostructures to achieve systematic targeting to intended sites and controlled release by different stimuli, including pH, redox, light, enzyme and so on. The use of DNA, proteins and other biomolecules opens a new gate to create smart nanocarriers for anti-cancer drugs.

Atherosclerosis treatments by gene regulation are garnering attention, yet delivery of gene cargoes to atherosclerotic plaques remains inefficient. Here, we demonstrate that assembly of therapeutic oligonucleotides into a three-dimensional spherical nucleic acid nanostructure improves their systemic delivery to the plaque and the treatment of atherosclerosis. This noncationic nanoparticle contains a shell of microRNA-146a oligonucleotides, which regulate the NF-κB pathway, for achieving transfection-free cellular entry. Upon an intravenous injection into apolipoprotein E knockout mice fed with a high-cholesterol diet, this nanoparticle naturally targets class A scavenger receptor on plaque macrophages and endothelial cells, contributing to elevated delivery to the plaques (∼1.2% of the injected dose). Repeated injections of the nanoparticle modulate genes related to immune response and vascular inflammation, leading to reduced and stabilized plaques but without inducing severe toxicity. Our nanoparticle offers a safe and effective treatment of atherosclerosis and reveals the promise of nucleic acid nanotechnology for cardiovascular disease.