SiExo: An AI-Driven Exosome Platform for Precision siRNA Delivery in CNS Disorders

Neurodegenerative diseases, including Huntington’s disease, Alzheimer’s disease, and Parkinson’s disease, are among the most challenging disorders to treat due to the restrictive nature of the blood-brain barrier (BBB), which blocks over 98% of potential therapeutics. Small interfering RNA (siRNA) presents a promising gene-silencing strategy, but clinical translation is hindered by degradation, off-target effects, and poor BBB permeability.This study presents SiExo, an AI-driven siRNA-loaded exosome platform engineered for high-efficiency CNS delivery. By integrating machine learning, molecular dynamics simulations, and Bayesian optimization, SiExo refines exosome lipid composition, ligand density, and siRNA stability for optimal therapeutic effect. Dual-ligand functionalization with transferrin and rabies virus glycoprotein enhances receptor-mediated BBB transcytosis, achieving a 3.5-fold increase in BBB penetration over unmodified exosomes. Functional testing in hCMEC/D3-based in vitro BBB models confirmed a 32% penetration rate (compared to 12% in controls, p < 0.01).AI-driven exosome design outperforms conventional lipid nanoparticles and viral vectors, yielding 2.8-fold greater siRNA retention and 1.9-fold higher neuron-specific uptake. In Huntington’s disease models, SiExo-mediated siRNA delivery resulted in a 62% reduction in mutant HTT mRNA expression, demonstrating significant gene-silencing potential. Bayesian optimization identified optimal exosome configurations with 92% predictive accuracy, accelerating non-immunogenic, patient-specific exosome engineering.This study establishes SiExo as a scalable CNS gene therapy platform, capable of supporting CRISPR/Cas9-based interventions for neurodegenerative and neuroinflammatory disorders. Future work will focus on in vivo validation and preclinical translation using patient-derived neural organoids and primate models, bridging the gap toward next-generation precision medicine for CNS disorders.