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.

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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.

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The previous research showed contradictions in the relationships between psychological flexibility processes and functioning. This meta-analysis is the first to provide a comprehensive meta-analysis of the associations between six core processes of psychological flexibility and functioning among chronic pain patients. Four databases were searched (PsycINFO; PubMed; CINAHL; Web of Science) along with reference lists. Thirty-six cross-sectional studies were included (7,812 chronic pain patients). A three-level meta-analytic model was used to examine the associations. The publication bias was assessed with the Egger test, funnel plot, and p-curve analysis. Significant associations were found between functioning and six processes of psychological flexibility (i.e., acceptance, defusion, present moment, committed action, self as context, and values). Except for the relationship between defusion and functioning, the relationships between the other five psychological flexibility processes and functioning were all moderated by domains of functioning. No moderators were found regarding age, percentage of females, country, or type of instrument used to measure functioning. These findings may carry significant implications for chronic pain patients and clinical workers. It might be more effective to focus on functioning-related psychological flexibility processes rather than all therapy packages if the relationships between functioning and specific processes of psychological flexibility were better informed. Limitations were also discussed.

Cerebrovascular dysfunction characterized by the neurovascular unit (NVU) impairment contributes to the pathogenesis of Alzheimer's disease (AD). In this study, a cerebrovascular‐targeting multifunctional lipoprotein‐biomimetic nanostructure (RAP‐RL) constituted with an antagonist peptide (RAP) of receptor for advanced glycation end‐products (RAGE), monosialotetrahexosyl ganglioside, and apolipoprotein E3 is developed to recover the functional NVU and normalize the cerebral vasculature. RAP‐RL accumulates along the cerebral microvasculature through the specific binding of RAP to RAGE, which is overexpressed on cerebral endothelial cells in AD. It effectively accelerates the clearance of perivascular Aβ, normalizes the morphology and functions of cerebrovasculature, and restores the structural integrity and functions of NVU. RAP‐RL markedly rescues the spatial learning and memory in APP/PS1 mice. Collectively, this study demonstrates the potential of the multifunctional nanostructure RAP‐RL as a disease‐modifying modality for AD treatment and provides the proof of concept that remodeling the functional NVU may represent a promising therapeutic approach toward effective intervention of AD.

Background: Parenting style has been extensively demonstrated as a predictor of depression in children and adolescents, but few studies have examined the antecedents of parenting style, especially parents’ beliefs towards children. The effect of parents’ implicit beliefs on children’s mental health is still unclear. This study aimed to explore the influence of parents’ value of children (VOC) on adolescent depression, and the underlying mechanism between parents’ VOC and adolescent depression.Methods: High school and college students and their parents were recruited to participate a cross-sectional online survey. The parents completed the VOC scale, and the adolescents completed the scales of parenting style, external LOC, self-esteem, and depression. A structural equation model was performed to analyze the multiple mediating effects on adolescent depression.Results: A total of 963 Chinese adolescents (Mage = 17.78 ± 1.94 years, 55.5% female) and their parents (Mage = 45.40 ± 4.40 years, 58% mothers) were recruited and examined in the current analysis. The results showed that the social and psychological benefits of VOC directly predict adolescent depression (βsocial benefits = 0.191, p < 0.001; βpsychological benefits = - 0.180, p < 0.001), whereas the relational benefits of VOC do not (βrelational benefits = - 0.027, p > 0.05). Moreover, the underlying mechanism and paths were examined between VOC, parenting style, external locus of control, self-esteem and depression.Conclusions: Our results enrich the theoretical framework of parents’ VOC on adolescent depression. It also provides valuable practical insights into parenting attitudes and beliefs, and highlighted the importance of VOC towards psychological benefits as a possible protective factor against depression in adolescence.