RNA-based medicines have transformed modern therapeutics, exemplified by the clinical success of small interfering RNAs (siRNAs), antisense oligonucleotides (ASOs), and mRNA vaccines. Small self-cleaving ribozymes - compact catalytic RNA species capable of programmable cleavage and ligation - were among the earliest RNA drugs explored, yet their progress was initially hindered by instability, nuclease degradation, inefficient intracellular delivery, and immune activation. In this Perspective, we discuss how recent technological convergence has revived their potential. Comparative genomics has uncovered new catalytic classes, including Twister, Pistol, Hatchet, and Hovlinc ribozymes, thereby expanding the catalytic repertoire. High-resolution structural and computational studies have elucidated their reaction architectures, while chemical modifications and advanced nanocarrier systems - such as DNA nanostructures, spherical nucleic acids, and lipid nanoparticles - have markedly improved molecular stability and delivery efficiency. Emerging applications, from ligand-responsive aptazymes and ribozyme-SNA conjugates to the StitchR RNA trans-ligation platform, further illustrate the expanding biomedical versatility of catalytic RNA. Together, these advances are redefining the role of ribozymes in oncology, virology, and genetic medicine. No longer a dormant concept, ribozymes now stand as an evolving frontier - rationally engineered catalysts that continue to inspire technological creativity and renewed optimism in RNA therapeutics.
