Rolling circle replication based nucleic acid nanostructures for programmable drug delivery

Nucleic acid nanostructures are powerful nanomaterials for biomedical applications owing to their inherent programmability, biocompatibility, and biodegradability. However, their usability has been limited by inefficient synthesis methods and their susceptibility to degradation in physiological environments. To overcome these challenges, rolling circle replication (RCR), an isothermal enzymatic reaction, has emerged as a polymerization method to generate ultra-long nucleic acid nanostructures with improved productivity, biostability, and functionality. This minireview provides a general overview of the versatile biological functions and engineering strategies for RCR based nucleic acid nanostructures. We also highlight recent advances in passive targeted delivery, active targeted delivery, and stimulus responsive delivery using polymeric DNA and RNA nanostructures. Finally, we outline the current status, key challenges, and future perspectives of nucleic acid nanostructures for advanced drug delivery.