Ionizable lipid nanoparticles (LNPs) have been widely used for in vivo delivery of RNA therapeutics into the liver. However, a main challenge remains to develop LNP formulations for selective delivery of RNA into certain types of liver cells, such as hepatocytes and liver sinusoidal endothelial cells (LSECs). Here, we report the engineered LNPs for the targeted delivery of RNA into hepatocytes and LSECs. The effects of particle size and polyethylene glycol–lipid content in the LNPs were evaluated for the hepatocyte-specific delivery of mRNA by ApoE-mediated cellular uptake through low-density lipoprotein receptors. Targeted delivery of RNA to LSECs was further investigated using active ligands. Incorporation of mannose allowed the selective delivery of RNA to LSECs, while minimizing the unwanted cellular uptake by hepatocytes. These results demonstrate that engineered LNPs have great potential for the cell type–specific delivery of RNA into the liver and other tissues.

DNA secondary structures, such as dimers and hairpins, are important for the synthesis of DNA templateembedded silver nanoclusters (DNA/AgNCs). However, the arrangement of AgNCs within a given DNA template and how the AgNC influences the secondary structure of the DNA template are still unclear. Here, we introduce a noncanonical head-to-head hairpin DNA nanostructure that is driven by orange-emissive AgNCs. Through detailed in-gel analysis, sugar backbone switching, inductively coupled plasma mass spectrometry, small-angle X-ray scattering, and small angle neutron scattering, we show that the orange-emissive AgNCs mediate cytosine-Ag-cytosine bridging between two six-cytosine loop (6C-loop) hairpin DNA templates. Unlike green, red, or far-red emissive AgNCs, which are embedded inside a hairpin and duplex DNA template, the orange-emissive AgNCs are localized on the interface between the two 6C-loop hairpin DNA templates, thereby linking them. Moreover, we found that deoxyribose in the backbone of the 6C-loop at the third and fourth cytosines is crucial for the formation of the orange-emissive AgNCs and the head-to-head hairpin DNA structure. Taken together, we suggest that the specific wavelength of AgNCs fluorescence is determined by the mutual interaction between the secondary or tertiary structures of DNA-and AgNC-mediated intermolecular DNA cross-linking.

Due to powerful breakthroughs in nanotechnology, smart delivery mechanisms have rapidly emerged for use in diverse applications across biomedical research and therapeutic development. Recent efforts toward understanding stimuli-responsive strategies have led to substantial improvements in their conceptual application and in vitro efficiency. Because disease targets for therapy are often localized in specific cells, organs, or tissues, an enhanced permeability and retention (EPR)-based strategy remains inadequate for accurate drug delivery and release to target regions, resulting in an insufficient drug concentration reaching the target region and undesired side effects. To address these issues, more precise and remote-controlled stimuli-responsive systems, which recognize and react to changes in the pathophysiological microenvironment, were recently elucidated as feasible on-demand drug-delivery systems. In this Perspective, we focus on progress toward stimuli-responsive drug-delivery systems that utilize dynamic DNA molecules by exploiting DNA nanotechnology. DNA structures can be precisely reconfigured by external and internal stimuli to drive the release of a loaded drug in a target region with appropriate microenvironments. We describe the chemical, physical, and biological engineering principles and strategies for constructing DNA-assisted nanocarriers. We also provide a summary of smart nanocarrier systems, organized with respect to the structural changes in the DNA strand in the microenvironment, resulting from changes in pH and temperature and the presence of intracellular oligonucleotides. To do so, we highlight recent advances in related biomedical research and applications as well as discuss major challenges and opportunities for DNA-assisted nanocarriers to guide the development of future in vivo therapies and clinical translation strategies.

The size-tunable polymerized DNA nanoparticles (PDNs) for cancer-targeted drug delivery were synthesized via sequential processes of rolling circle amplification, condensation, and layer-by-layer assembly.