Abstract: Rare diseases are mostly caused by genetic mutations and are commonly associated with diagnostic difficulties, limited treatment options, and substantial shortcomings of conventional therapies. Gene therapy has emerged as an important therapeutic strategy for these diseases. Virus-like particles (VLPs), as promising biomimetic delivery vehicles, have demonstrated considerable potential for the treatment of rare diseases. This review first systematically describes the fundamental structural characteristics and classification of VLPs. Following a detailed discussion of the sequential process of specific receptor binding, cellular uptake, endosomal trafficking, endosomal escape, and cargo release, it analyzes and summarizes multidimensional engineering strategies for improving the structural stability, targeting ability, and cargo-loading capacity of VLPs. In addition, the therapeutic applications of VLPs in three rare diseases—X-linked chronic granulomatous disease, Leber congenital amaurosis, and Huntington’s disease—are reviewed. This review provides a reference for the future design and application of VLP-based delivery systems.