Protein Nanocages as Versatile Vectors for Nucleic Acid Delivery: Main Systems and Their Loading Mechanisms

The rapid advancement of nucleic acid-based technologies, such as mRNA vaccines and CRISPR-based gene editing, has transformed modern medicine. Yet, their full therapeutic potential remains constrained by the need for precise cargo loading and efficient delivery. This limitation has inspired the development of novel vector systems capable of both protecting nucleic acids and directing them to specific cellular targets. Protein nanocages have emerged as a highly versatile and programmable class of delivery vectors. Considerable research has focused on repurposing and engineering various platforms, including virus-like particles, encapsulins, and ferritins, to serve as robust nanocarriers. Using innovative strategies, researchers have developed sophisticated cargo-loading mechanisms that have evolved from simple electrostatic attraction to high-specificity, affinity-based systems that mimic viral packaging. At the same time, a deeper understanding of how nucleic acids interact with the nanocage interior is revealing some key structural factors that drive efficient packaging. In this review, we highlight the key advances in the design and application of protein nanocages for nucleic acid delivery. We analyze the primary systems and their distinct loading mechanisms, discuss current challenges, and explore future directions to help establish engineered nanomaterials as a new and powerful category of medical therapies.