Nucleic acid–based therapeutics, like small interfering RNA (siRNA), could be instrumental in treating diseases that are considered to be “untreatable” by small molecule drugs. The identification of genes important in some neurodegenerative disease shows promise for this area of research, but the delivery of siRNA across the blood-brain barrier (BBB)—and into the brain—remain a challenge. Now, a nanoparticle platform has been developed that can facilitate delivery in mice. Indeed, in a mouse model of traumatic brain injury (TBI), the delivery system showed three times more accumulation in the brain than conventional methods. This work suggests that this nanoparticle platform may be a promising next-generation drug delivery approach for the treatment of TBI.

The work is published in Science Advances and is titled, “BBB pathophysiology–independent delivery of siRNA in traumatic brain injury.”

“To be able to deliver agents across the BBB in the absence of inflammation has been somewhat of a holy grail in the field,” said co-senior author Jeff Karp, PhD, professor of medicine at Brigham and Women’s Hospital, Harvard Medical School. “Our radically simple approach is applicable to many neurological disorders where delivery of therapeutic agents to the brain is desired.”

TBI is a leading cause of death and disability among children and young adults, with millions of people sustaining TBI each year in accidents, sports, and military conflicts. Not only does TBI contribute to the development of potentially long-lasting neurological dysfunctions, memory disturbances, behavioral changes, speech irregularities, and gait abnormalities, it has also been implicated in the development of neurodegenerative disease, particularly chronic traumatic encephalopathy, Alzheimer’s disease, and Parkinson’s disease.

Previously developed approaches for delivering therapeutics into the brain after TBI rely on the short window of time after a physical injury to the head, when the BBB is temporarily breached. However, after the BBB is repaired within a few weeks, physicians lack tools for effective drug delivery.

“It’s very difficult to get both small and large molecule therapeutic agents delivered across the BBB,” said corresponding author Nitin Joshi, PhD, an associate bioengineer at the Center for Nanomedicine in the Brigham’s department of anesthesiology, perioperative and pain medicine. “Our solution was to encapsulate therapeutic agents into biocompatible nanoparticles with precisely engineered surface properties that would enable their therapeutically effective transport into the brain, independent of the state of the BBB.”

The siRNA molecule in this study was designed to inhibit the expression of the tau protein, which is believed to play a key role in neurodegeneration. Poly(lactic-co-glycolic acid), or PLGA, a biodegradable and biocompatible polymer used in several existing products approved by the FDA, was used as the base material for nanoparticles. The researchers engineered a unique nanoparticle design that maximized the transport of the encapsulated siRNA across the intact BBB and significantly improved the uptake by brain cells.

“In addition to demonstrating the utility of this novel platform for drug delivery into the brain, this report establishes for the first time that systematic modulation of surface chemistry and coating density can be leveraged to tune the penetration of nanoparticles across biological barriers with tight junction,” said first author Wen Li, PhD, of the department of anesthesiology, perioperative and pain medicine.

A 50% reduction in the expression of tau was observed in TBI mice who received anti-tau siRNA through the novel delivery system, irrespective of the formulation being infused within or outside the temporary window of breached BBB. In contrast, tau was not affected in mice that received the siRNA through a conventional delivery system.

Rebekah Mannix, MD, MPH, senior associate physician in medicine at Boston Children’s Hospital, associate professor, pediatrics and emergency medicine, Harvard Medical School, and a co-senior author on the study, further emphasized that the BBB inhibits delivery of therapeutic agents to the central nervous system (CNS) for a wide range of acute and chronic diseases. “The technology developed for this publication could allow for the delivery of large number of diverse drugs, including antibiotics, antineoplastic agents, and neuropeptides,” she said. “This could be a game-changer for many diseases that manifest in the CNS.”

In addition to targeting tau, the researchers have studies underway to attack alternative targets using the novel delivery platform.

“For clinical translation, we want to look beyond tau to validate that our system is amenable to other targets,” Karp said. “We used the TBI model to explore and develop this technology, but essentially anyone studying a neurological disorder might find this work of benefit. We certainly have our work cut out, but I think this provides significant momentum for us to advance toward multiple therapeutic targets and be in the position to move ahead to human testing.”

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