Engineered small extracellular vesicles as bioactive materials: Integrating engineering strategies for cargo loading and targeted delivery systems

Small extracellular vesicles (sEVs) are increasingly regarded as a unique class of bioactive materials whose intrinsic membrane composition and nanoscale architecture provide a versatile platform for therapeutic engineering. Rather than passive carriers, sEVs can be actively programmed through diverse strategies to achieve efficient loading, precise targeting, and functional integration with synthetic systems. Endogenous modulation of donor cells—via genetic editing, priming with bioactive glass, cytokine stimulation, or hypoxic cues—enables selective packaging of nucleic acids, proteins, and metabolites into secreted vesicles. Exogenous techniques, including electroporation, sonication, and extrusion, allow controlled incorporation of therapeutic drugs or genome-editing complexes such as CRISPR/Cas. In parallel, surface modifications based on Lamp2b-fusion scaffolds, aptamers, antibodies, and click chemistry confer tissue tropism and extend circulation time. Integration with nanomaterials, scaffolds, and microfluidic platforms further enhances stability, scalability, and reproducibility, positioning sEVs at the intersection of biology and materials science. This review highlights recent advances in engineering sEVs as programmable bioactive materials and discusses their potential to transform regenerative medicine, oncology, and precision therapeutics. Engineered sEVs as Multifunctional Bioactive MaterialsEngineering strategies transform natural sEVs into programmable nanocarriers through integrated cargo-loading and surface-modification techniques. Combining biological processes with material-based cues enhances targeting, stability, and therapeutic potency, positioning sEVs as next-generation bioactive materials for precision medicine. • Engineered sEVs enable precise therapeutic delivery with enhanced biocompatibility and targeting. • Integrates material design, manufacturing, and regulatory roadmap for clinical translation. • Addresses key challenges: endosomal escape, large cargo confinement, and immune stealth. • Demonstrates efficacy across cancer, neurodegeneration, and regenerative models.