Chemically modified nucleic acid nanodevices: molecular engineering for drug delivery, theranostics, biosensing and...

The intrinsic programmability of nucleic acids has positioned them as versatile molecular building blocks for constructing nanodevices with significant diagnostic and therapeutic potential. However, the clinical translation of these constructs is severely hindered by major pharmacokinetic (PK) and biophysical limitations, including susceptibility to enzymatic degradation, short circulation half-life, and inefficient cellular uptake. Chemical modification, encompassing nucleobase engineering, backbone and sugar-ring alterations, terminal conjugation, and higher-order structural reinforcement, provides a powerful strategy to overcome these barriers by enhancing in vivo stability, prolonging circulation, improving cellular internalization, and enabling stimulus-responsive cargo release. In this review, we summarize recent advances in chemically modified nucleic acid nanodevices, focusing on how specific chemical designs modulate physicochemical properties, improve pharmacokinetics, enable organ- or cell-selective targeting, and enable spatiotemporally controlled molecular release. We further highlight their emerging applications in precision drug delivery, high-sensitivity biosensing, and integrated theranostics. Finally, we critically discuss persistent translational challenges, including batch-to-batch scalability, immunogenicity, and long-term nanotoxicity, and propose forward-looking solutions, such as AI-assisted design, to pave the way for industrial adoption and clinical implementation.