Intranasal drug delivery of small interfering RNA targeting Beclin1 encapsulated with polyethylenimine (PEI) in mouse brain to achieve HIV attenuation

The researchers aimed to overcome the blood-brain barrier (BBB) to develop a non-invasive therapeutic strategy for HIV-associated neurological complications. Specifically, they investigated whether intranasal administration of Beclin1-targeting siRNA, encapsulated in a biodegradable cationic polymer (PEI), could safely and effectively reach the central nervous system and silence the targeted gene.

The team utilized a mouse model to test the bio-distribution and safety of the PEI-siRNA nano-complex. After confirming the formation of the complex using Raman spectroscopy, they administered it intranasally. They used fluorescence imaging to track the delivery, immunolabeling to identify the target cell types (neurons, microglia, and astrocytes), and Western blotting to quantify gene silencing efficiency in brain regions such as the prefrontal cortex. Potential neurotoxicity was assessed through histological examination of brain and lung tissues.

The researchers successfully demonstrated that intranasal delivery allows for rapid and widespread distribution of the PEI-siRNA complex into the brain, reaching both neurons and glial cells within hours. Treatment with the Beclin1-targeting nanoplex resulted in significant, temporary depletion of Beclin1 protein expression in the brain without causing signs of neurotoxicity or inducing an inflammatory immune response in the brain or lungs. The study provides a proof-of-concept that this delivery mechanism can effectively bypass the BBB to achieve gene silencing in the CNS.

Current antiretroviral therapies for HIV often struggle to penetrate the BBB effectively, leaving behind viral reservoirs in the brain that can contribute to cognitive impairment and neurological damage. By using a non-invasive, intranasal approach with a safe, biodegradable polymer, this study offers a promising framework for gene-silencing therapies that could potentially reduce viral replication and inflammation directly within the CNS.