Stimuli‐Responsive Nucleic Acid‐Based Polyacrylamide Hydrogel‐Coated Metal–Organic Framework Nanoparticles for Controlled Drug Release

TLDR

The authors develop a general method to synthesize doxorubicin‑loaded metal–organic framework nanoparticles coated with a stimuli‑responsive nucleic‑acid‑based polyacrylamide hydrogel, overcoming limitations of prior nucleic‑acid‑gated NMOFs. The hydrogel is formed by crosslinking two polyacrylamide chains functionalized with nucleic‑acid hairpins through a strand‑induced hybridization chain reaction, incorporating a caged anti‑ATP aptamer that degrades in the presence of ATP overexpressed in cancer cells to release the encapsulated drug. The hydrogel‑coated NMOFs achieve higher drug loading, prevent nonspecific leakage, and selectively kill MDA‑MB‑231 breast cancer cells while sparing normal MCF‑10A epithelial cells.

Abstract

Abstract The synthesis of doxorubicin‐loaded metal–organic framework nanoparticles (NMOFs) coated with a stimuli‐responsive nucleic acid‐based polyacrylamide hydrogel is described. The formation of the hydrogel is stimulated by the crosslinking of two polyacrylamide chains, P A and P B , that are functionalized with two nucleic acid hairpins ( 4 ) and ( 5 ) using the strand‐induced hybridization chain reaction. The resulting duplex‐bridged polyacrylamide hydrogel includes the anti‐ATP (adenosine triphosphate) aptamer sequence in a caged configuration. The drug encapsulated in the NMOFs is locked by the hydrogel coating. In the presence of ATP that is overexpressed in cancer cells, the hydrogel coating is degraded via the formation of the ATP–aptamer complex, resulting in the release of doxorubicin drug. In addition to the introduction of a general means to synthesize drug‐loaded stimuli‐responsive nucleic acid‐based polyacrylamide hydrogel‐coated NMOFs hybrids, the functionalized NMOFs resolve significant limitations associated with the recently reported nucleic acid‐gated drug‐loaded NMOFs. The study reveals substantially higher loading of the drug in the hydrogel‐coated NMOFs as compared to the nucleic acid‐gated NMOFs and overcomes the nonspecific leakage of the drug observed with the nucleic‐acid‐protected NMOFs. The doxorubicin‐loaded, ATP‐responsive, hydrogel‐coated NMOFs reveal selective and effective cytotoxicity toward MDA‐MB‐231 breast cancer cells, as compared to normal MCF‐10A epithelial breast cells.