Abstract: Rare diseases are often caused by genetic mutations and commonly face challenges such as difficulty in diagnosis, limited effectiveness of traditional therapies, and significant inherent shortcomings. Current research indicates that gene therapy has become one of the key strategies for tackling these diseases. Among these, virus-like particles (VLPs), by means of their precise targeting, excellent biocompatibility, and high efficiency in intracellular delivery, have emerged as highly promising novel biomimetic delivery systems. Based on this, the authors systematically explain how VLPs achieve precise intracellular delivery of therapeutic payloads through a delivery mechanism of "specific receptor binding–cellular endocytosis–endosomal transport–escape and release." Through multi-dimensional engineering modifications, it is possible to optimize self-assembly efficiency, targeting ability, and endosomal escape capability, thereby improving gene transfection efficiency and enhancing therapeutic outcomes. Taking X-linked chronic granulomatous disease, Leber congenital amaurosis, and Huntington’s disease as application examples, the potential of VLPs in rare disease treatment is further demonstrated. Although the development and application of VLPs still face many challenges at present, by integrating cutting-edge technologies such as synthetic biology and directed evolution and employing rational design to improve their structural stability, targeting specificity, and payload capacity, VLPs are expected to become a core tool for achieving precise treatment of rare diseases.