Abstract Regenerative medicine in tissue engineering often relies on stem cells and specific growth factors at a supraphysiological dose. These approaches are costly and may cause severe side effects. Herein, therapeutic small extracellular vesicles (t‐sEVs) endogenously loaded with a cocktail of human vascular endothelial growth factor A (VEGF‐A) and human bone morphogenetic protein 2 (BMP‐2) mRNAs within a customized injectable PEGylated poly (glycerol sebacate) acrylate (PEGS‐A) hydrogel for bone regeneration in rats with challenging femur critical‐size defects are introduced. Abundant t‐sEVs are produced by a facile cellular nanoelectroporation system based on a commercially available track‐etched membrane (TM‐nanoEP) to deliver plasmid DNAs to human adipose‐derived mesenchymal stem cells (hAdMSCs). Upregulated microRNAs associated with the therapeutic mRNAs are enriched in t‐sEVs for enhanced angiogenic–osteogenic regeneration. Localized and controlled release of t‐sEVs within the PEGS‐A hydrogel leads to the retention of therapeutics in the defect site for highly efficient bone regeneration with minimal low accumulation in other organs.
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