Endogenous retroviruses (ERVs) are remnants of retroviral infections that have become stably integrated into host germline genomes. Far beyond passive genomic elements, ERVs actively shape host evolution through complex mechanisms involving genetic innovation, immune modulation, and species adaptation. This review provides a comprehensive synthesis of ERV biology, highlighting recent advances in their classification, amplification mechanisms, and epigenetic silencing. Particular emphasis is placed on the cross-talk between ERVs and exogenous retroviruses (XRVs), demonstrating how receptor competition, recombination, and immune evasion contribute to virus-host co-evolution. We explore ERVs as molecular markers for phylogenetic reconstruction, with case studies such as Koala retrovirus (KoRV) and HERV-K illustrating regional transmission dynamics and co-opted immune functions. Additionally, we discuss the functional domestication of ERVs into regulatory elements, non-coding RNAs, and envelope-derived fusion proteins that influence gene expression, antiviral defense, and placental development.

Once dismissed as mere cellular waste, extracellular vesicles (EVs) have undergone a conceptual redefinition, emerging as programmable therapeutic scaffolds with broad biomedical applications. Modern EVs design has progressed past the conventional framework of localized cargo delivery to isolated recipient cells; instead, the focus has shifted toward systemic, multi-cellular niche remodeling aimed at restoring tissue-level homeostasis. This review provides a comprehensive analysis of the engineering strategies to overcome the biological bottlenecks of naive EVs, specifically rapid systemic clearance and inefficient cytosolic delivery. We detail current strategies for active loading and for bypassing endolysosomal entrapment to facilitate in-situ translation of therapeutic mRNA. Furthermore, we discuss how the synergy between engineered EVs and responsive biomaterial scaffolds provides the spatiotemporal control necessary for localized reprogramming of diseased microenvironments. Finally, by examining application paradigms across oncology, regenerative medicine, and neurodegeneration alongside existing regulatory classification frameworks, this review provides a roadmap for transitioning intelligent vesicle platforms from benchtop discovery to clinical-grade compliance.