BBB pathophysiology independent delivery of siRNA in traumatic brain injury

Abstract

Small interfering RNA (siRNA) represents a powerful strategy to mitigate the long-term sequelae of traumatic brain injury (TBI). However, poor permeability of siRNA across the blood brain barrier (BBB) poses a major hurdle. One approach to overcome this challenge involves treatment administration while the BBB is physically breached post-injury. However, this approach is only applicable to a subset of injuries with substantial BBB breach and can lead to variable therapeutic response due to the heterogeneity of physical breaching of BBB in TBI. Moreover, since physical breaching of BBB is transient, this approach offers a limited window for therapeutic intervention, which is not ideal as repeated dosing beyond the transient window of physically breached BBB might be required. Herein, we report a nanoparticle platform for BBB pathophysiology-independent delivery of siRNA in TBI. We achieved this by combined modulation of surface chemistry and coating density, which maximized the active transport of nanoparticles across BBB. Intravenous injection of engineered nanoparticles, within or outside the window of physically breached BBB in TBI mice resulted in 3-fold higher brain accumulation compared to conventional PEGylated nanoparticles and demonstrated up to 50% gene silencing. To our knowledge, this is the first reported example of BBB pathophysiology-independent drug delivery in TBI, and the first time combined modulation of surface chemistry and coating density has been shown to tune BBB penetration of nanoparticles. Taken together, our approach offers a clinically relevant approach to develop siRNA therapeutics for preventing long-term effects of TBI and deserves further exploration.

Polysorbate-Based Drug Formulations for Brain-Targeted Drug Delivery and Anticancer Therapy

“…PS 80-coated PLGA NPs were developed for the efficient transport of small interfering RNA (siRNA) across the BBB in traumatic brain injury (TBI) [142] (Figure 10). siRNA-based therapeutics can mitigate disease progression in TBI treatment, but siRNA suffers from poor BBB transport.…”

“…As a result, tau siRNA-loaded PS 80-coated PLGA NPs significantly suppressed tau expression in cultured primary neural cells. Additionally, they achieved efficient tau silencing in TBI mice with no systemic toxicity when administered during the early or late injury period [142]. PS 80-coated PLGA NPs were developed for the efficient transport of small interfering RNA (siRNA) across the BBB in traumatic brain injury (TBI) [142] (Figure 10).…”

A Nanomule Peptide Carrier Delivers siRNA Across the Intact Blood-Brain Barrier to Attenuate Ischemic Stroke

“…Thus they never reach the CNS in significant amounts to have a biological outcome, and this may lead to poor efficacy in a clinical setting. Some examples exist for the entry of free siRNA ( Xie et al, 2020 ) or siRNA-encapsulated nanoparticles ( Li et al, 2021 ) to enter the CNS, however, to date these intriguing approaches are only described to exert their therapeutic effect after a prior breach of the BBB and do not directly show transcytosis of the intact BBB. For example, some studies on traumatic brain injury indicate that BBB may be breached for several days after induction of trauma ( Li et al, 2021 ), others indicate the BBB is permeable for weeks after initial injury (e.g., ischemia, blunt force trauma) ( Strbian et al, 2008 ; Price et al, 2016 ), and some BBB tight junction components can be downregulated for up to 8 weeks ( Nag et al, 2007 ).…”

“…Some examples exist for the entry of free siRNA ( Xie et al, 2020 ) or siRNA-encapsulated nanoparticles ( Li et al, 2021 ) to enter the CNS, however, to date these intriguing approaches are only described to exert their therapeutic effect after a prior breach of the BBB and do not directly show transcytosis of the intact BBB. For example, some studies on traumatic brain injury indicate that BBB may be breached for several days after induction of trauma ( Li et al, 2021 ), others indicate the BBB is permeable for weeks after initial injury (e.g., ischemia, blunt force trauma) ( Strbian et al, 2008 ; Price et al, 2016 ), and some BBB tight junction components can be downregulated for up to 8 weeks ( Nag et al, 2007 ). In addition, observation of brain penetration in Alzheimer’s disease and Multiple Sclerosis models have shown a prior breach in the BBB as part of the pathogenesis of the disease ( Ujiie et al, 2003 ; Bennett et al, 2010 ; Biron et al, 2011 ; Biron et al, 2013 ), and siRNA studies in these models similarly cannot be used to conclude transcytosis of siRNA across an intact BBB ( Zhou et al, 2020 ).…”

Nanotechnology‐Assisted RNA Delivery: From Nucleic Acid Therapeutics to COVID‐19 Vaccines

“…[ 49 , 50 , 51 , 52 , 53 ] Furthermore, the effect of siRNAs in neurological disorders has been studied to effectively inhibit targeted gene expression in the central nervous system by specific gene silencing. [ 54 , 55 ] Additionally, GalNAc‐siRNA conjugates are exploited for efficient siRNA delivery to liver hepatocytes, inducing targeted gene silencing while guaranteeing the duration of the effect. [ 56 ] Lastly, the suitability of siRNA‐therapeutics in cardiovascular diseases has also been proved.…”