Nature-derived exosome-like nanoparticles (NELNs) for intracellular transport and targeted RNA delivery

As exosomes serve as pivotal mediators of intercellular communication, research on exosomes has expanded markedly from its conventional focus on mammalian sources to the burgeoning field of nature-derived exosome-like nanoparticles (NELNs). Endowed with favorable biocompatibility, low immunogenicity, and wide, readily accessible sources, NELNs have emerged as promising delivery vehicles to address long-standing bottlenecks in RNA-based therapeutic delivery. However, their clinical translation is significantly impeded by the lack of a consensus definition and standardized manufacturing workflows. This review focuses on NELNs-mediated therapeutic RNA delivery; systematic delineation of NELNs' characteristics and biogenic pathways remains insufficient, and further investigation is warranted for details of NELNs' properties, including biochemical composition, inherent biological functions, in vivo biodistribution regulated by distinct administration routes, cellular uptake mechanisms, and regulatory pathways of targeted delivery, as well as state-of-the-art strategies for the construction and optimization of RNA-loaded NELNs. This review systematically characterizes the intracellular trafficking, cargo release kinetics, and metabolic degradation profiles of NELNs-RNA complexes, summarizes their therapeutic applications in brain disorders, intestinal diseases, and tumors, analyzes critical translational challenges including scalable production, batch-to-batch consistency, long-term safety, and targeting precision, and proposes rational optimization strategies to advance mechanistic research and clinical translation of NELNs-based RNA delivery systems.