BBB pathophysiology independent delivery of siRNA in traumatic brain injury

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.Competing Interest StatementJMK has been a paid consultant and or equity holder for multiple biotechnology companies (listed here https://www.karplab.net/team/jeff-karp). The interests of JMK were reviewed and are subject to a management plan overseen by his institutions in accordance with its conflict of interest policies. N.J., J.MK., W.L., R.M., J.Q. and R.L. have one unpublished patent based on the nanoparticle work presented in this manuscript. For a list of entities with which R.L. is involved, compensated or uncompensated, see www.dropbox.com/s/yc3xqb5s8s94v7x/Rev%20Langer%20COI.pdf?dl=0.View Full Text