Controlled delivery of a neurotransmitter-agonist conjugate for functional recovery after severe spinal cord injury.

Despite considerable unmet medical needs, effective pharmacological treatments that promote functional recovery after spinal cord injury remain limited. Although multiple pathological events are implicated in spinal cord injuries, the development of a microinvasive pharmacological approach that simultaneously targets the different mechanisms involved in spinal cord injury remains a formidable challenge. Here we report the development of a microinvasive nanodrug delivery system that consists of amphiphilic copolymers responsive to reactive oxygen species and an encapsulated neurotransmitter-conjugated KCC2 agonist. Upon intravenous administration, the nanodrugs enter the injured spinal cord due to a disruption in the blood-spinal cord barrier and disassembly due to damage-triggered reactive oxygen species. The nanodrugs exhibit dual functions in the injured spinal cord: scavenging accumulated reactive oxygen species in the lesion, thereby protecting spared tissues, and facilitating the integration of spared circuits into the host spinal cord through targeted modulation of inhibitory neurons. This microinvasive treatment leads to notable functional recovery in rats with contusive spinal cord injury.

Downregulation of UBE4B promotes CNS axon regrowth and functional recovery after stroke.

The limited intrinsic regrowth capacity of corticospinal axons impedes functional recovery after cortical stroke. Although the mammalian target of rapamycin (mTOR) and p53 pathways have been identified as the key intrinsic pathways regulating CNS axon regrowth, little is known about the key upstream regulatory mechanism by which these two major pathways control CNS axon regrowth. By screening genes that regulate ubiquitin-mediated degradation of the p53 proteins in mice, we found that ubiquitination factor E4B (UBE4B) represses axonal regrowth in retinal ganglion cells and corticospinal neurons. We found that axonal regrowth induced by UBE4B depletion depended on the cooperative activation of p53 and mTOR. Importantly, overexpression of UbV.E4B, a competitive inhibitor of UBE4B, in corticospinal neurons promoted corticospinal axon sprouting and facilitated the recovery of corticospinal axon-dependent function in a cortical stroke model. Thus, our findings provide a translatable strategy for restoring corticospinal tract-dependent functions after cortical stroke.

Porous microneedle patch with sustained delivery of extracellular vesicles mitigates severe spinal cord injury.

The transplantation of mesenchymal stem cells-derived secretome, particularly extracellular vesicles is a promising therapy to suppress spinal cord injury-triggered neuroinflammation. However, efficient delivery of extracellular vesicles to the injured spinal cord, with minimal damage, remains a challenge. Here we present a device for the delivery of extracellular vesicles to treat spinal cord injury. We show that the device incorporating mesenchymal stem cells and porous microneedles enables the delivery of extracellular vesicles. We demonstrate that topical application to the spinal cord lesion beneath the spinal dura, does not damage the lesion. We evaluate the efficacy of our device in a contusive spinal cord injury model and find that it reduces the cavity and scar tissue formation, promotes angiogenesis, and improves survival of nearby tissues and axons. Importantly, the sustained delivery of extracellular vesicles for at least 7 days results in significant functional recovery. Thus, our device provides an efficient and sustained extracellular vesicles delivery platform for spinal cord injury treatment.

Rationally Designed, Self-Assembling, Multifunctional Hydrogel Depot Repairs Severe Spinal Cord Injury.

Following severe spinal cord injury (SCI), dysregulated neuroinflammation causes neuronal and glial apoptosis, resulting in scar and cystic cavity formation during wound healing and ultimately the formation of an atrophic microenvironment that inhibits nerve regrowth. Because of this complex and dynamic pathophysiology, a systemic solution for scar- and cavity-free wound healing with microenvironment remodeling to promote nerve regrowth has rarely been explored. A one-step solution is proposed through a self-assembling, multifunctional hydrogel depot that punctually releases the anti-inflammatory drug methylprednisolone sodium succinate (MPSS) and growth factors (GFs) locally according to pathophysiology to repair severe SCI. Synergistically releasing the anti-inflammatory drug MPSS and GFs in the hydrogel depot throughout SCI pathophysiology protects spared tissues/axons from secondary injury, promotes scar boundary- and cavity-free wound healing, and results in permissive bridges for remarkable axonal regrowth. Behavioral and electrophysiological studies indicate that remnants of spared axons, not regenerating axons, mediate functional recovery, strongly suggesting that additional interventions are still required to render the rebuilt neuronal circuits functional. These findings pave the way for the development of a systemic solution to treat acute SCI.