A primer on prime: A prime editing update from advances to first-in-human trial.

The advent of CRISPR systems has transformed genome editing, offering unparalleled efficiency and versatility with wide therapeutic potential. However, conventional CRISPR systems face key limitations, including unpredictable and imprecise outcomes during repair of double-stranded breaks and reliance on specific protospacer adjacent motif sequences. In response, prime editing (PE) has emerged as a powerful alternative, enabling precise custom edits using a fusion of Cas9 nickase and an engineered reverse transcriptase (RT) together with a PE guide RNA (pegRNA) that encodes the desired repair template. PE enables edits to be installed at or downstream of the target site, expanding the range of targetable sequences. Since its inception, PE has undergone extensive optimization, including Cas variant selection, RT engineering, and pegRNA improvements. In parallel, advances in delivery, including nanoparticles and split viral systems, have accelerated translation across preclinical disease models. Notably, PE has now entered the clinic, with the first-in-human study reporting functional restoration with a promising safety profile to date. Here, we summarize recent mechanistic insights, architectural innovations, and therapeutic applications of PE and discuss the remaining challenges in efficiency, delivery, and safety that will shape broader clinical impact.