Extracellular vesicles spread SHANK3-linked hyperexcitability and iPSC EVs reverse deficits in mice
Feb 22nd 2026
EVs from SHANK3-deficient human iPSC cortical neurons transfer hyperexcitability and accelerated maturation to control neurons in vitro. EVs from mesenchymal stem cells and healthy iPSCs normalize neuronal activity and intranasal iPSC-EV treatment rescues ASD-like behaviors in Shank3B knockout mice.
- EVs from SHANK3-deficient human iPSC-derived cortical neurons transfer hyperexcitability and accelerated maturation phenotypes to control neurons in vitro.
- Proteomic analysis shows mutant neuron EVs are enriched for synaptic structural regulators including ACTB, CFL1, AGRN, and CLSTN1, consistent with actin cytoskeletal dysregulation.
- EVs from control neurons fail to rescue SHANK3 mutant phenotypes, likely because they are less enriched for synaptic proteins and related pathways.
- EVs from mesenchymal stem cells and healthy donor iPSCs rescue hyperexcitability and normalize maturation in SHANK3 mutant neurons and contain complement proteins, plasticity-associated proteins, and homeostatic regulators such as C1R, C1S, MDK, IGFBP3, FGF2, and SFRP1.
- Intranasal delivery of iPSC-derived EVs to Shank3B knockout mice significantly rescues ASD-like behavioral deficits, demonstrating in vivo efficacy.
- Authors propose an EV-mediated mechanism for modulating dysregulated excitability and synaptic maturation and highlight EVs as a potential therapeutic avenue for ASD and related neurodevelopmental disorders.