Journal
NANO LETTERS
Volume 22, Issue 8, Pages 3400-3409Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.nanolett.2c00667
Keywords
DNA nanotechnology; nanomedicine; mechanotransduction; motor proteins; cell nucleus
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Funding
- Research Grants Council (RGC) [14300120]
- National Natural Science Foundation of China (NSFC)/RGC Joint Research Scheme grant [N_CUHK434/16]
- Chow Yuk Ho Technology Centre for Innovative Medicine at The Chinese University of Hong Kong (CUHK)
- Croucher Innovation Award from the Croucher Foundation
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This study demonstrates the use of extracellular mechanical stimuli to enhance the delivery of DNA nanostructures to the nucleus. Gentle compression of mammalian cells with polythymidine-rich nucleic acids increases nuclear accumulation without causing severe endosomal entrapment or membrane damage. This method shows potential for applications in intranuclear gene therapies.
DNA nanostructures are attractive gene carriers for nanomedicine applications, yet their delivery to the nucleus remains inefficient. We present the application of extracellular mechanical stimuli to activate cellular mechanotransduction for boosting the intranuclear delivery of DNA nanostructures. Treating mammalian cells with polythymidine-rich spherical nucleic acids (poly(T) SNAs) under gentle compression by a single coverslip leads to up to similar to 50% nuclear accumulation without severe endosomal entrapment, cytotoxicity, or long-term membrane damage; no chemical modification or transfection reagent is needed. Gentle compression activates Rho-ROCK mechanotransduction and causes nuclear translocation of YAP. Joint compression and treatment with poly(T) oligonucleotides upregulate genes linked to myosin, actin filament, and nuclear import. In turn, Rho-ROCK, myosin, and importin mediate the nuclear entry of poly(T) SNAs. Treatment of endothelioma cells with poly(T) SNAs bearing antisense oligonucleotides under compression inhibits an intranuclear oncogene. Our data should inspire the marriage of DNA nanotechnology and cellular biomechanics for intranuclear applications.
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