RNA-based nanomedicines encompass a range of therapeutic approaches that utilize RNA molecules or molecules that target RNAs for the treatment or prevention of diseases. These include antisense oligonucleotides (ASOs), small interfering RNAs (siRNAs), endogenous microRNAs (miRNAs), messenger RNAs (mRNAs), clustered regularly interspersed short palindromic repeats-associated protein 9 (CRISPR/Cas9), single guide RNAs (sgRNAs), as well as RNA aptamers. These therapeutic agents exert their effects through various mechanisms such as gene inhibition, addition, replacement, and editing. The advancement of RNA biology and the field of RNA therapy has paved the way for the development and utilization of RNA-based nanomedicine in human healthcare. One remarkable example of RNA-based nanomedicine is the mRNA-based vaccines including mRNA-1273 (Moderna) and BNT162b2 (Pfizer/BioNTech) that have been successfully employed in response to the coronavirus disease 2019 (COVID-19) pandemic. This review aims to highlight the advantages of RNA-based nanomedicines, provides an overview of significant developments in delivery systems, elucidates the molecular mechanisms of action underlying RNA-based nanomedicines, and discusses their clinical applications. Additionally, the review will address the existing challenges and innovations in delivery platforms while exploring the future possibilities for these promising RNA-based nanomedicines.