Rolling circle amplification/transcription-based nanotechnology for efficient delivery of nucleic acid drugs

Rolling circle amplification/transcription (RCA/RCT) nanotechnology offers a breakthrough platform for nucleic acid drug delivery, leveraging enzymatically produced ultra-long, programmable nucleic acid chains to engineer multifunctional nanostructures. In this review, we give an overview of RCA/RCT-based nanocarriers for nucleic acid drug delivery, systematically summarizing their key design aspects: (1) nanoization strategies through biomineralization, electrostatic compression, nanomaterial-assisted assembly and base pairing/entanglement; (2) drug loading approaches via design on template, complementary base pairing and electrostatic binding; (3) targeting modalities including aptamers, proteins, polymers and small molecule ligands; and (4) controlled release mechanisms responsive to endogenous/exogenous enzymes and intracellular microenvironments. We showcase their significant therapeutic advances in gene therapy, immunotherapy, and combination therapy. This overview provides critical insights for developing next-generation RCA/RCT delivery platforms to address pressing biomedical needs.