Nanocarrier-mediated siRNA delivery: a new approach for the treatment of traumatic brain injury-related Alzheimer's disease

Abstract

Traumatic brain injury and Alzheimer's disease share pathological similarities, including neuronal loss, amyloid-β deposition, tau hyperphosphorylation, blood-brain barrier dysfunction, neuroinflammation, and cognitive deficits. Furthermore, traumatic brain injury can exacerbate Alzheimer's disease-like pathologies, potentially leading to the development of Alzheimer's disease. Nanocarriers offer a potential solution by facilitating the delivery of small interfering RNAs across the blood-brain barrier for the targeted silencing of key pathological genes implicated in traumatic brain injury and Alzheimer's disease. Unlike traditional approaches to neuroregeneration, this is a molecular-targeted strategy, thus avoiding non-specific drug actions. This review focuses on the use of nanocarrier systems for the efficient and precise delivery of siRNAs, discussing the advantages, challenges, and future directions. In principle, siRNAs have the potential to target all genes and non-targetable proteins, holding significant promise for treating various diseases. Among the various therapeutic approaches currently available for neurological diseases, siRNA gene silencing can precisely "turn off" the expression of any gene at the genetic level, thus radically inhibiting disease progression; however, a significant challenge lies in delivering siRNAs across the blood-brain barrier. Nanoparticles have received increasing attention as an innovative drug delivery tool for the treatment of brain diseases. They are considered a potential therapeutic strategy with the advantages of being able to cross the blood-brain barrier, targeted drug delivery, enhanced drug stability, and multifunctional therapy. The use of nanoparticles to deliver specific modified siRNAs to the injured brain is gradually being recognized as a feasible and effective approach. Although this strategy is still in the preclinical exploration stage, it is expected to achieve clinical translation in the future, creating a new field of molecular targeted therapy and precision medicine for the treatment of Alzheimer's disease associated with traumatic brain injury.

Figure 1

The illustration delineates the pathological links between TBI and AD. TBI and AD share analogous pathological hallmarks, including amyloid plaque deposition, neurofibrillary tangle formation, neuroinflammation, and cognitive impairment. Concurrently, various nanocarriers are employed to deliver siRNAs, primarily traversing the BBB via receptor-mediated transcytosis and tight junction exploitation. Upon crossing the BBB and localization of the target site, the nanocarriers release their siRNA cargo. Within the RNA-induced silencing complex, the guide strand of the siRNA duplex associates with the Argonaute protein. The RISC-bound guide strand then undergoes sequence-specific base-pairing with the target mRNA. Subsequently, the Argonaute protein cleaves and rapidly degrades the recognized mRNA, preventing its translation into the corresponding protein, thereby inducing potent gene silencing. Created with WPS 12.1.0.16929. AD: Alzheimer’s disease; BBB: blood–brain barrier; RISC: RNA-induced silencing complex; siRNA: small interfering RNA; TBI: traumatic brain injury

Figure 2

A timeline for the progression of therapeutic advances from TBI and AD correlation studies and nanocarrier-delivered siRNAs in research. Created with WPS 12.1.0.16929. AD: Alzheimer’s disease; FDA: Food and Drug Administration; LNP: lipid nanoparticle; siRNA: small interfering RNA; TBI: traumatic brain injury.

Figure 3

The illustration of the pathophysiolog course of TBI. TBI can be caused by either focal brain injury or diffuse brain injury resulting in an initial injury. After the initial injury, TBI may trigger a series of secondary injuries, including axonal damage, hydrocephalus, mitochondrial dysfunction, oxidative stress, and neuroinflammation. Created with WPS 12.1.0.16929. TBI: Traumatic brain injury.