Extracellular vesicles from adipose-derived stem cells in bone regeneration: Mechanisms and therapeutic advances

Table 2 Preclinical Strategies of adipose-derived stem cell-derived extracellular vesicles in osteoarthritis

Pretreated cells/modified EVs	Strategy	In vivo model	Delivery route	Effects in vivo	Ref.
ADSCs stimulated with ↓TNF-α & IFN-γ to ADSC-EVs	MiR-27b-3p enriched EVs + SF scaffold	Rabbit TMJ condylar defect	Scaffold implantation	↑BMSC proliferation, osteo-/chondrogenesis; ↑M2 macrophages; ↓inflammation; ↑bone/cartilage repair	[22]
PEMF-stimulated rat ADSC-EVs	PEMF stimulation (15-75 Hz) to enhance EVs	ACLT rat OA model	IA injection (40 μL, weekly × 4)	↑Anabolic cartilage markers; ↓MMP-13, IL-1β; ↑histology scores; ↓inflammation	[23]
ADSC-EVs enriched with miR-486-5p (miR-486-5p mimic-transfected ADSCs)	Engineered EVs delivering miR-486-5p	DMM rat OA model	IA injection (20 μL, weekly × 10)	↓Chondrocyte apoptosis, MMP-13, inflammation; ↑COL II, cartilage matrix; ↓OARSI score	[24]
Curcumin-loaded ADSC-EVs	Drug-loading to enhance antioxidant & anti-apoptosis	ACLT mouse model	IA injection (10 μL, biweekly × 4)	↓Cartilage degeneration, oxidative stress, apoptosis, pain; ↑ECM components (COL II, aggrecan)	[27]
ADSC-EVs enriched with miR-376c-3p	MiR-376c-3p delivery targeting WNT/β-catenin	MIA rat OA model	IA injection (100 μg EVs, single dose)	↓Cartilage degradation, fibrosis, inflammatory cytokines; ↑COL II; WNT signaling inhibition	[90]
ADSC-EVs (unmodified)	Native EVs isolated by TFF	MIA-induced rat OA model	IA injection (30 μL, weekly × 3 or 6)	↓Mankin score, cartilage erosion, inflammatory markers; ↑cartilage matrix protection	[91]
ADSC-EVs (unmodified)	Native EVs isolated by TFF	DMM mouse OA model	IA injection (6 μL, weekly × 6)	↓OARSI score, synovial inflammation, M1 macrophages; ↑COL II, chondrocyte proliferation/migration	[91]

EVs: Extracellular vesicles; ADSC: Adipose-derived stem cell; TNF-α: Tumor necrosis factor-alpha; IFN-γ: Interferon-gamma; ADSC-EVs: Adipose-derived stem cell-derived extracellular vesicles; miR-27b-3p: MicroRNA-27b-3p; SF: Silk fibroin; TMJ: Temporomandibular joint; BMSC: Bone marrow mesenchymal stem cells; PEMF: Pulsed electromagnetic field; ACLT: Anterior cruciate ligament transection; OA: Osteoarthritis; IA: Intra-articular; MMP-13: Matrix metalloproteinase-13; IL-1β: Interleukin-1β; miR-486-5p: MicroRNA-486-5p; DMM: Destabilization of the medial meniscus; COL II: Collagen type II; OARSI: Osteoarthritis Research Society International; ECM: Extracellular matrix; miR-376c-3p: MicroRNA-376c-3p; MIA: Monosodium iodoacetate; TFF: Tangential flow filtration.