Proton‐Mediated Dynamic Nestling of DNA Payloads Within Size‐Matched MOFs Nanochannels for Smart Intracellular Delivery

Abstract With sequence‐programmable biological functions and excellent biocompatibility, synthetic functional DNA holds great promise for various biological applications. However, it remains a challenge to simultaneously retain their biological functions while protecting these fragile oligonucleotides from the degradation by nucleases abundant in biological circumstances. Herein, a smart delivery system for functional DNA payloads is developed based on proton‐mediated dynamic nestling of cytosine‐rich DNA moieties within the precisely size‐matched nanochannels of highly crystalline metal–organic frameworks (MOFs): At neutral pH, cytosine‐rich DNA strands exhibit a flexible single‐stranded state and can be accommodated by MOFs nanochannels with a size of ca. 2.0 nm; while at acidic conditions, the protonation of cytosine‐rich strands weakens their interaction with the nanochannels, and the tendency to form four‐stranded structures drives these DNA strands out of the nanochannels. Results confirm the successful protection of DNA payloads from enzymatic hydrolysis by the MOFs nanochannels, and the delicate coupling of the endocytosis processes and the proton‐responsive Cytosine‐rich DNA/MOFs systems realized the efficient intracellular delivery of DNA payloads. Furthermore, with a complementary sequence to the telomere overhangs, direct imaging of telomeres and the nucleus is successfully achieved with the proton‐mediated DNA/MOFs system.