Nucleus-forming phages: from subcellular organization and viral-host interplay to prospects for phage applications

The increasing emergence of multidrug-resistant bacterial infections poses a major threat to humankind, with 10 million deaths predicted in 2050 as a result. Phage therapy has therefore regained attention as a promising approach to combat these pathogens. However, the ongoing evolutionary arms race between phages and bacteria has driven the accumulation of phage defense systems in bacterial populations, which can compromise the efficacy and generalizability of phage applications. Recently, nucleus-forming phages have been discovered and classified under the newly established phage family 'Chimalliviridae'. Chimalliviruses orchestrate a highly organized, nucleus-based replication that physically segregates phage DNA from host defenses, thereby enhancing replication efficiency and conferring resistance to a wide array of host defenses. Their unique replication strategy and subcellular organization far exceed that of classical phages, positioning them as candidates for a new class of 'next-generation phages' with superior therapeutic potential and biocontrol capabilities. This review will cover the current landscape of chimallivirus discovery, highlighting their association with bacterial pathogens, unique replication machinery, and interaction with bacterial defenses. Furthermore, it provides insights into chimallivirus-based therapeutic applications.