Extracellular Vesicle-Liposome-Darunavir Formulation for the Treatment of HIV Neuropathogenesis

This study evaluates the efficacy of an extracellular vesicles-liposome-darunavir (EV-Lip-DRV) formulation for the treatment of HIV neuropathogenesis, including neurocognitive disorders. The EV-Lip-DRV formulation was developed through a process involving thin-film hydration and extrusion, followed by ultrafiltration to remove unloaded DRV. The encapsulation efficiency was found to be 41.75 ± 2.19%, with a particle size of ∼189 nm and zeta potential of ∼-7.8 mV. The hemocompatibility test confirmed the safety of the formulation for red blood cells, while drug release profiles demonstrated a sustained release of DRV within 24 h. Our <i>in vitro</i> experiment showed that EV-Lip-DRV significantly reduces HIV replication in U1 macrophages and alters the pro-inflammatory cytokine and chemokine levels. Pharmacokinetic studies in C57BL/6 mice via intranasal administration revealed significantly enhanced drug delivery in the brain, relative to systemic circulation and other peripheral organs. Behavioral studies using EcoHIV-infected mice indicated significant improvements in HIV-associated impaired cognitive and motor functions when treated with the EV-Lip-DRV formulation compared to those with DRV alone. Furthermore, analysis of brain tissues from these mice showed significantly reduced HIV-associated inflammatory response, oxidative stress, DNA damage, and neuronal damage in EV-Lip-DRV as compared with DRV alone. Taken together, these findings suggest that EV-Lip is a promising vehicle for enhancing the delivery of antiretroviral drugs to the brain, potentially ameliorating symptoms associated with HIV neuropathogenesis and improving overall outcomes in HIV treatment.