Advanced Small Extracellular Vesicles Delivery Systems for In Situ Tissue Engineering
Summary: Published March 12, 2026 in Extracellular Vesicles and Circulating Nucleic Acids (OAE Publishing, Vol. 7, pp. 354–376), this comprehensive review from Peking University School and Hospital of Stomatology and Peking University Third Hospital systematically covers the state of the art in small extracellular vesicle (sEV) delivery systems for in situ tissue engineering — an approach that activates the body’s innate regenerative capacity by implanting bioactive materials rather than transplanting pre-constructed grafts. sEVs (30–150 nm diameter) are natural nanovesicles secreted by virtually all cell types, carrying lipids, proteins, DNA, RNA, and microRNAs that mediate intercellular communication and regulate immune responses, angiogenesis, and tissue regeneration. Their key advantages — low immunogenicity, multi-target regulatory capability, and ability to cross biological barriers — make them promising cell-free alternatives in regenerative medicine. However, their therapeutic efficacy is dose-dependent and their rapid clearance by the mononuclear phagocyte system (liver, spleen, kidneys) when administered systemically or locally limits therapeutic sustainability. The review covers sEVs derived from mesenchymal stem cells (BMSCs, ADSCs, DPSCs), immune cells, endothelial cells, body fluids (platelet-rich plasma, milk), and plant-derived vesicle-like nanoparticles (PELNs from ginger, ginseng, purslane). For delivery systems, it categorises scaffold-based approaches (physical adsorption onto 3D-printed PLA, β-TCP, PLGA, PCL, titanium, and hydroxyapatite scaffolds; affinity coating using polydopamine, PEI, heparin, tannic acid, and calcium phosphate) and hydrogel-based approaches (direct physical entrapment in silk fibroin, GelMA, chitosan/ZnO, PEG hydrogels; chemical immobilisation via carbodiimide crosslinkers or CP05 fusion peptides targeting CD63). Applications in wound healing include ADSC-sEV acceleration of diabetic wound repair, HUVEC-sEV promotion of angiogenesis, microneedle patch delivery in diabetic wound models, and CP05-mediated sEV anchoring to hydrogels for granulation tissue formation. Future directions discussed include long-term sustained release systems and environmentally responsive (pH-, temperature-, enzyme-triggered) release platforms.
Key Highlights:
- sEV sources compared: MSC-derived (BMSC, ADSC, DPSC) for bone, immune, and wound healing; HUVEC-derived for angiogenesis; platelet-rich plasma for anti-inflammatory and pro-angiogenic effects; plant-derived PELNs for anti-inflammatory and gut microbiota modulation
- Scaffold delivery strategies: physical adsorption (simple but burst-releasing) vs. affinity coating using polydopamine, PEI, calcium phosphate — PDA and biomineralised scaffolds enable sustained sEV release for up to 21 days
- Hydrogel strategies: direct encapsulation (silk fibroin, GelMA, chitosan/ZnO-NPs for diabetic wound dressings) vs. covalent immobilisation via CP05 fusion peptides targeting CD63 on sEV surface — enables more sustained, controlled retention at wound site
- Wound healing applications: ADSC-sEVs regulate Keap1/Nrf2 axis in diabetic wound fibroblasts; HUVEC-sEVs combined with tazarotene accelerate cell proliferation and tube formation; microneedle-MOF platforms deliver antimicrobial effect plus sEV-mediated tissue repair
- Responsive release: hydrogel-embedded sEVs can be engineered for pH-, temperature-, enzyme-, and electrical-responsive release — aligning drug delivery with the dynamic phases of wound healing (inflammation, proliferation, remodelling)
- Key challenges: large-scale sEV production yield, standardisation of preparations, long-term release kinetics optimisation, and clinical translation from preclinical models to human trials
Keywords: extracellular vesicles wound healing, exosome wound care, sEV diabetic wound healing, hydrogel wound dressing drug delivery, in situ tissue engineering wound, stem cell exosome angiogenesis
Yike Gao, Jingyi Sang, Yuming Zhao, Yue Wang, Zuoying Yuan