Delivery of proteins to carry out desired biological functions is a direct approach for disease treatment. However, protein therapy is still facing challenges due to low delivery efficiency, poor targeting during trafficking, insufficient therapeutic efficacy, and possible toxicity induced by carriers. Here, we present a novel delivery platform based on DNA origami nanostructure that enables tumor cell transportation of active proteins for cancer therapy. In our design, cytotoxic protein ribonuclease (RNase) A molecules are organized on the rectangular DNA origami nanosheets, which work as nanovehicles to deliver RNase A molecules into the cytoplasm and execute their cell-killing function inside the tumor cells. Cancer cell-targeting aptamers are also integrated onto the DNA origami-based nanoplatform to enhance its targeting effect. This DNA origamiprotein coassembling strategy can be further developed to transport other functional proteins and therapeutic components simultaneously for synergistic effects and be adapted for integrated diagnostics and therapeutics.
Enzymes fold into three-dimensional structures to arrange their active groups exquisitely for the remarkable catalytic properties. We are inspired to design and assemble Gln-containing peptides with G-quadruplex DNA/hemin complexes to form the catalytic nanofibrils that possess the horseradish peroxidase-mimicking active sites and catalytic functions. Theoretical simulation results revealed that the intermolecular association of Gln peptide may result in local enrichment and proper orientation of carboxamide groups, which provide potential multivalent hydrogen bonds for enhancing H2O2 affinity to hemin and may behave similarly to distal Arg in a natural heme pocket. The self-folded DNA can provide a guanine base as the axial ligand, and a supramolecular scaffold for supporting and orienting hemin. The β-sheet forming capability of the Q peptides is found to significantly affect the catalytic synergy between the G-DNA and the peptide. The role of hydrogen bonds network provided by self-assembled Gln peptides is illustrated by solvent kinetic isotope effects and H2O2-induced degradation of hemin. The assembly of the Q peptide with G-DNA/hemin DNAzyme also stimulates the chiroselective oxidization of L-DOPA vs D-DOPA. The incorporation of His-containing peptide into the hemin system via self-assembly, which was demonstrated by confocal colocalization images and fluorescence resonance electron transfer results, further enhanced the catalytic activity of the G-DNA/Q peptide/hemin complex. It is hypothesized that the assembly of the triple components allows mimicking the configuration and the function of the catalytic His-Arg-His triad in horseradish peroxidase. Compared to DNA/hemin or peptide/hemin, the catalytic efficiency of the most active complex shows 10-fold enhanced activity. This work opens an avenue to mimic the catalytic residues and their spatial distribution and may provide a primitive enzyme model for the evolution of modern enzymes. Our results may also have implications for the mechanisms of some cell dysfunctions, which are triggered by catalytic aggregation of biomolecules.
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