This work highlights a multifunctional nanoscale material which can effectively compartmentalize small molecules and biomolecules into a single, micellar structure with programmable degradation properties resulting in highly controllable release properties. The nanomaterial consists of a ZIF-8 metal organic framework (MOF) encapsulated within a DNA surfactant micelle assembly, referred to as a nucleic acid nanocapsule (NAN). NANs have been demonstrated to enter cells through endocytosis and result in intracellular cargo release upon enzyme-triggered degradation. By combining the favorable properties of MOFs (large storage capacity) with those of NANs (triggerable release), we show diverse molecular cargo can be integrated into a single, highly programmable nanomaterial with controllable release profiles. The hybrid MOF–NANs exhibit double-gated regulation capabilities as evidenced by kinetic studies of encapsulated enzymes that indicate individual layers of the particle influence the overall enzymatic rate of turnover. The degradation of MOF–NANs can be controlled under multiple combined stimuli (i.e. varying pH, enzymes), enabling selective release profiles in solutions representative of more complex biological systems. Lastly, the enhanced control over the release of small molecules, proteins and plasmids, is evaluated through a combination of cell culture and in vitro fluorescence assays, indicating the potential of MOF–NANs for both therapeutic and diagnostic applications.

Allergic asthma is one of the leading chronic lung diseases of both children and adults worldwide, resulting in significant morbidity and mortality in affected individuals. Many patients have severe asthma, which is refractory to treatment, illustrating the need for the development of new therapeutics for this disease. Herein, we describe the use of a peptide cross-linked nucleic acid nanocapsule (NAN) for the delivery of a GATA3-specific DNAzyme to immune cells, with demonstration of modulated transcriptional activity and behavior of those cells. The NAN, built from peptide cross-linked surfactants, is chemically designed to degrade under inflammation conditions releasing individual DNAzyme-surfactant conjugates in response to proteolytic enzymes. Using the NAN, GATA3 DNAzymes were delivered efficiently to human peripheral blood mononuclear cells, with clear evidence of uptake by CD4+ helper T cells without the need for harsh transfection agents. Knockdown of GATA3 was achieved in vitro using human Jurkat T cells, which express GATA3 under homeostatic conditions. Additionally, mice treated with DNAzyme-NANs during house dust mite (HDM)-induced asthma developed less severe allergic lung inflammation than HDM-only control mice, as measured by pulmonary eosinophilia. This study suggests that peptide cross-linked GATA3 DNAzyme-NANs may have the potential to decrease the severity of asthma symptoms in human patients, and development of this technology for human use warrants further investigation.