Another approach to clinical implementation of exosomes is as biologically active carriers, providing a platform for enhanced delivery of cargo in vivo. Due to exosomes’ intricate structure, engineering them to be effective and safe requires thorough understanding of their necessary components, including, but not limited to, membrane stability, architecture, organization, and packaging of the interior components [
85]. Using biologically derived exosomes as a starting point, groups have worked to re-engineer exosomes to contain small molecule inhibitors, functional genomic material, reporter systems, and targeting peptides, among many others [
86,
87]. In all of these cases, toxicity and immunogenicity concerns should be taken into consideration – it has been demonstrated that exosomes derived from stromal cells, such as fibroblasts and DCs, may be effective [
88]. In one study, fibroblast-derived exosomes with high CD47 expression were engineered to carry short interfering or short hairpin RNA specific to oncogenic
KrasG12D expression. In mouse models of pancreatic cancer, these engineered exosomes ablated oncogenic KRAS signaling, slowed tumor growth, and increased overall survival [
89]. Other studies have also demonstrated exosome-like lipoplexes can efficiently deliver RNA to that is capable of systemically activating dendritic cells. In a phase I dose-escalation trial of this technology, melanoma patients treated at low doses displayed strong antigen-specific T-cell responses [
90]. As cancer immunotherapy becomes standard-of-care for various cancers, similar exosome-based vaccination or therapeutic delivery strategies will become increasingly important. This therapeutic possibility has been explored in post-transplantation treatment, utilizing exosomes to prime mesenchymal stem cells for recovery [
91].