Mengna Zheng

Despite the various mechanisms that involved in the pathogenesis of Alzheimer's disease (AD), neuronal damage and synaptic dysfunction are the key events leading to cognition impairment. Therefore, neuroprotection and neurogenesis would provide essential alternatives to the rescue of AD cognitive function. Here we demonstrated that extracellular vesicles secreted from adipose-derived mesenchymal stem cells (ADSCs-derived EVs, abbreviated as EVs) entered the brain quickly and efficiently following intranasal administration, and majorly accumulated in neurons within the central nervous system (CNS). Proteomics analysis showed that EVs contained multiple proteins possessing neuroprotective and neurogenesis activities, and neuronal RNA sequencing showed genes enrichment in neuroprotection and neurogenesis following the treatment with EVs. As a result, EVs exerted powerful neuroprotective effect on Aβ1–42 oligomer or glutamate-induced neuronal toxicity, effectively ameliorated neurologic damage in the whole brain areas, remarkably increased newborn neurons and powerfully rescued memory deficits in APP/PS1 transgenic mice. EVs also reduced Aβ deposition and decreased microglia activation although in a less extent. Collectively, here we provide direct evidence that ADSCs-derived EVs may potentially serve as an alternative for AD therapy through alleviating neuronal damage and promoting neurogenesis.

Brain drug delivery is one of the most important bottlenecks in the development of drugs for the central nervous system. Cumulative evidence has emerged that extracellular vesicles (EVs) play a key role in intercellular communication. Exosomes, a subgroup of EVs, have received the most attention due to their capability in mediating the horizontal transfer of their bioactive inclusions to neighboring and distant cells, and thus specifically regulating the physiological and pathological functions of the recipient cells. This native and unique signaling mechanism confers exosomes with great potential to be developed into an effective, precise, and safe drug delivery system. Here, we provide an overview into the challenges of brain drug delivery and the function of exosomes in the brain under physiological and pathological conditions, and discuss how these natural vesicles could be harnessed for brain drug delivery and for the therapy of brain diseases.

The secondary damage in traumatic brain injury (TBI) can lead to lifelong disabilities, bringing enormous economic and psychological burden to patients and their families. Mitochondria, as the core mediator of the secondary injury cascade reaction in TBI, is an important target to prevent the spread of cell death and dysfunction. Thus, therapeutics that can accumulate at the damaged sites and subsequently rescue the functions of mitochondria would largely improve the outcome of TBI. Cyclosporine A (CsA), which can maintain the integrity of mitochondrial function, is among the most promising neuroprotective therapeutics for TBI treatment. However, the clinical application of CsA in TBI is largely hindered because of its poor access to the targets. Here, to realize targeted intracellular CsA delivery, we designed a lipoprotein biomimetic nanocarrier by incorporating CsA in the core and decorating a matrix metalloproteinase-9 activatable cell-penetrating peptide onto the surface of the lipoprotein-mimic nanocarrier. This CsA-loaded tailored reconstituted lipoprotein efficiently accumulated at the damaged brain sites, entered the target cells, bound to the membrane of mitochondria, more efficiently reduced neuronal damage, alleviated neuroinflammation, and rescued memory deficits at the dose 1/16 of free CsA in a controlled cortical impact injury mice model. The findings provide strong evidence that the secondary damages in TBI can be well controlled through targeted CsA delivery and highlight the potential of a lipoprotein biomimetic nanocarrier as a flexible nanoplatform for the management of TBI.

The clinical application of extracellular vesicles (EVs)-based therapeutics continues to be challenging due to their rapid clearance, restricted retention, and low yields. Although hydrogel possesses the ability to impede physiological clearance and increase regional retention, it typically fails to effectively release the incorporated EVs, resulting in reduced accessibility and bioavailability. Here an intelligent hydrogel in which the release of EVs is regulated by the proteins on the EVs membrane is proposed. By utilizing the EVs membrane enzyme to facilitate hydrogel degradation, sustained retention and self-stimulated EVs release can be achieved at the administration site. To achieve this goal, the membrane proteins with matrix degrading activity in the mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) are identified using comparative proteomics. After that, a hydrogel comprised of self-assembled peptides that are susceptible to degradation by the membrane enzymes present in MSC-EVs is designed and synthesized. After intranasal administration, this peptide hydrogel facilitates sustained and thermo-sensitive release of MSC-EVs, thereby extending the retention of the MSC-EVs and substantially enhancing their potential for treating Alzheimer's disease. This research presents a comparative proteomics-driven approach to intelligent hydrogel design, which holds the capacity to significantly enhance the applicability of EVs in clinical settings.