Rethinking delivery routes: oral administration of plant-derived exosome-like nanovesicles reduces the toxicity of intravenous injection

Plant-derived exosome-like nanovesicles (PELNs), as an emerging "green" nanoplatform, exhibit broad pharmacological activities, low immunogenicity, and inherent advantages as natural drug carriers. They show great potential in the pharmaceutical, cosmetic, and health supplement sectors. The clinical application of PELNs is heavily contingent on their safety profile, which is intricately linked to the administration route. This opinion compares the safety implications of the two primary routes: oral administration versus intravenous injection. Current evidence indicates that intravenous administration of PELNs triggers complement activation, immune responses, and hepatorenal toxicity; even surface engineering modifications cannot completely eliminate these risks. In contrast, oral administration of PELNs may achieve superior safety by leveraging the gastrointestinal tract's ability to effectively reduce the immunogenic components. Based on these findings, we advocate for the prioritization of oral delivery in the future development of PELNs, given its superior safety profile for realizing their potential as natural therapeutics and drug delivery systems.