BACKGROUND:Decompressive craniectomy has been widely evaluated across heterogeneous types of brain injury but its effect in patients with large acute epidural haematoma complicated by tentorial herniation remains unclear. We aimed to assess whether decompressive craniectomy improves functional and safety outcomes compared with standard craniotomy in this patient group. METHODS:The Prospective Randomised Evaluation of Decompressive Ipsilateral Craniectomy for Traumatic Acute Epidural Haematoma (PREDICT-AEDH) trial was a nationwide, multicentre, open-label, parallel-group, randomised controlled trial conducted at 28 hospitals in China. Adults aged 18-65 years with clinical signs of transtentorial herniation, CT-confirmed large acute epidural haematoma, and obliterated ambient cistern within 12 h of injury were randomly assigned (1:1) to primary decompressive craniectomy or standard craniotomy with bone-flap replacement, using a secure, central, web-based randomisation system with block sizes of four. Although masking of patients and surgeons was not feasible, all assessments and analyses were done by masked investigators. The primary outcome was functional status at 6 months in all randomised patients according to intention to treat (ITT), assessed using the Glasgow Outcome Scale-Extended (GOSE) and analysed with a proportional-odds model. No imputation for missing outcome data was done since no participants were lost to follow-up. Safety outcomes were assessed in the ITT population. The trial is registered with ClinicalTrials.gov (NCT04261673) and is complete. FINDINGS:Between Sept 7, 2020, and March 14, 2025, 142 patients were screened for eligibility, of whom 120 patients (15 [12%] females and 105 [88%] males) were randomly assigned to decompressive craniectomy (n=58) or standard craniotomy (n=62). One patient assigned to the decompressive craniectomy group received craniotomy and ten patients assigned to craniotomy received decompressive craniectomy. At 6 months, a favourable functional outcome (GOSE ≥5) occurred in 46 (79%) of 58 patients assigned to decompressive craniectomy and 52 (84%) of 62 patients assigned to standard craniotomy. Ordinal analysis of GOSE failed to show a significant difference between groups (common OR 0·79 [0·41-1·58]; p=0·51). Rates were similar between the decompressive craniectomy and standard craniotomy groups for 30-day mortality (five [9%] of 58 patients vs three [5%] of 62 patients) and postoperative cerebral infarction (11 [19%] vs 11 [18%]). Delayed intracranial haemorrhage occurred more frequently after decompressive craniectomy (21 [36%] of 58 patients) than after standard craniotomy (eight [13%] of 62 patients; OR 3·79, 95% CI 1·43-11·00; p=0·0049). INTERPRETATION:In patients with large acute epidural haematoma and tentorial herniation, decompressive craniectomy did not improve 6-month functional outcomes compared with standard craniotomy and increased the risk of delayed intracranial haemorrhage. These findings therefore do not support routine prophylactic decompressive craniectomy in this population. FUNDING:None.

Traumatic brain injury (TBI) frequently leads to brain edema, a life-threatening complication and a major cause of mortality and disability. Here, we report that fenofibrate (FFB), an agonist of the nuclear receptor peroxisome proliferator-activated receptor-α (PPARα), alleviates post-traumatic brain edema by enhancing blood-brain barrier (BBB) integrity in a mouse model of severe TBI. Mechanistic studies in cultured endothelial cells and endothelial-specific PPARα conditional knockout mice revealed that FFB activates PPARα, enhances mitochondrial oxidative phosphorylation (OXPHOS), and thereby reduces oxidative stress and endothelial cell apoptosis. These findings identify PPARα-dependent enhancement of energy metabolism in the brain endothelium as a promising therapeutic strategy for TBI-induced edema.

The burden of traumatic brain injury (TBI) remains a challenge worldwide, and also in China. Since 2019, considerable changes in the epidemiology and characteristics of TBI have occurred, driven by social and economic factors, such as population ageing and the increasing use of mopeds for road transportation. Concurrently, substantial progress has been made in clinical research, including the implementation of high-quality studies on innovative treatments, such as long-term mild hypothermia for severe TBI, right median nerve stimulation for awakening patients in coma after a brain injury, and middle meningeal artery embolisation for chronic subdural haematoma. However, challenges remain, including in the establishment of training for neurosurgical residents, regional disparities in access to specialised healthcare, and low participation in international research networks. Clinical and other innovations provide opportunities for improving TBI care and research in China. Advances in China could offer guidance for the transition between TBI care in low-resource setting and highly specialised centres.

The blood-brain barrier (BBB) poses a significant challenge for the intravenous delivery of drugs targeting central nervous system (CNS) diseases. Recently, a novel adeno-associated virus (AAV)-9 variant, AAV.CAP-B10, has shown promise due to its high BBB-crossing efficiency and low liver toxicity. However, its strain dependency, ability to transduce the brain following cerebral lateral ventricle (CLV) injection, and underlying mechanisms remain unclear. In this study, we intravenously administered AAV.CAP-B10 to C57BL/6 and BALB/c mice to evaluate its ability to cross the BBB. We also injected AAV.CAP-B10 into the CLV of both mouse strains to assess brain transduction and explored its mechanisms using ciliobrevin D, a dynein inhibitor. Additionally, we tested whether AAV.CAP-B10 could deliver the nerve growth factor (Ngf) gene to treat traumatic brain injury (TBI) in mice. Our results showed that intravenous AAV.CAP-B10 effectively crossed the BBB in C57BL/6 mice but not in BALB/c mice. Brain transduction via CLV was significantly reduced in ciliobrevin D-treated mice, implicating dynein in this process. Furthermore, AAV.CAP-B10-mediated Ngf gene expression improved hippocampal function in TBI mice. These findings highlight the strain-dependent BBB penetration of AAV.CAP-B10, its dynein-associated hippocampal transduction via CLV, and its potential as a therapeutic gene vector for TBI treatment.

Microglia play a critical role in neuroinflammation, a key secondary injury mechanism following traumatic brain injury (TBI). The colony-stimulating factor 1 receptor (CSF-1R) inhibitor PLX5622 has shown promise in suppressing neuroinflammation by depleting microglia, but it lacks specificity in targeting microglia at the injury site. To overcome this limitation, we developed PLX5622 nanoparticles functionalized with the CAQK peptide for lesion-specific targeting and combined them with a hydrogel (GelMA-PPS) that possesses potent reactive oxygen species (ROS) scavenging capabilities. This nanoparticle-hydrogel drug delivery system (GelMA-PPS/P) significantly enhanced the delivery efficiency and therapeutic efficacy of PLX5622 in TBI treatment. Localized administration of this system effectively depleted microglia at the injury site, suppressed neuroinflammation, and reduced the release of inflammatory cytokines. Its ROS scavenging ability was also validated in vitro and in vivo. Together, these effects synergistically improved neurological function recovery in TBI mouse models. This innovative strategy offers a comprehensive and targeted approach to managing neuroinflammation after TBI, providing a promising avenue for advancing TBI therapies.

Traumatic brain injury (TBI) induces neuronal death, inflammation, and neurological dysfunction. Although nerve growth factor (NGF) possesses neuroprotective potential, its clinical use is hindered by poor blood-brain barrier (BBB) permeability and insufficient neural targeting. Here, a neurophilic biomimetic lipoprotein for brain-targeted NGF delivery is developed: 1) a matrix-like core (Nc) that preserves NGF bioactivity; 2) an ApoE3-reconstituted high-density lipoprotein shell (Nc-rHDL) to enhance BBB penetration; 3) an αRDP peptide-modified version (Nc-rHDL@P) to improve neural targeting. In vitro BBB models and controlled cortical impact (CCI) mice demonstrate that Nc-rHDL@P efficiently crossed the BBB and selectively accumulated around injured regions. The engineered Nc-rHDL@P significantly enhances the survival of injured neurons, promotes neurite outgrowth in PC12 cells, and facilitates the neuronal differentiation of human neural stem cells (hNSCs) and Schwann cells in vitro. In vivo studies confirm that Nc-rHDL@P effectively alleviated inflammation and glial scar formation while significantly increasing neuronal survival-ultimately facilitating the recovery of motor function, spatial learning, and memory in CCI model mice. Collectively, this neurophilic biomimetic lipoprotein platform demonstrates broad potential for brain-targeted delivery of neurotrophins beyond NGF, offering a promising translational strategy for TBI and related neurological disorders.

The dismal prognosis for glioblastoma multiform (GBM) patients is primarily attributed to the highly invasive tumor residual that remained after surgical intervention. The development of precise intraoperative imaging and postoperative residual removal techniques will facilitate the gross total elimination of GBM. Here, a self-disassembling porphyrin lipoprotein-coated calcium peroxide nanoparticles (PLCNP) is developed to target GBM via macropinocytosis, allowing for fluorescence-guided surgery of GBM and improving photodynamic treatment (PDT) of GBM residual by alleviating hypoxia. By reducing self-quenching and enhancing lysosome escape efficiency, the incorporation of calcium peroxide (CaO2) cores in PLCNP amplifies the fluorescence intensity of porphyrin-lipid. Furthermore, the CaO2 core has diminished tumor hypoxia and improves the PDT efficacy of PLCNP, enabling low-dose PDT and reversing tumor progression induced by hypoxia aggravation following PDT. Taken together, this self-disassembling and oxygen-generating porphyrin-lipoprotein nanoparticle may serve as a promising all-in-one nanotheranostic platform for guiding precise GBM excision and empowering post-operative PDT, providing a clinically applicable strategy to combat GBM in a safe and effective manner.

Both therapeutic hypothermia and neural stem cells (NSCs) transplantation have shown promise in neuroprotection and neural repair after brain injury. However, the effects of therapeutic hypothermia on neuronal differentiation of NSCs are not elucidated. In this study, we aimed to investigate whether mild hypothermia promoted neuronal differentiation in cultured and transplanted human NSCs (hNSCs). A significant increase in neuronal differentiation rate of hNSCs was found when exposed to 35 degrees C, from 33% to 45% in vitro and from 7% to 15% in vivo . Additionally, single -cell RNA sequencing identified upregulation of RNA -binding motif protein 3 (RBM3) in neuroblast at 35 degrees C, which stabilized the SRY-box transcription factor 11 (SOX11) mRNA and increased its protein expression, leading to an increase in neuronal differentiation of hNSCs. In conclusion, our study highlights that mild hypothermia at 35 degrees C enhances hNSCs-induced neurogenesis through the novel RBM3-SOX11 signaling pathway, and provides a potential treatment strategy in brain disorders.

Background Cerebral hemorrhage is a critical medical condition that necessitates a rapid and precise diagnosis for timely medical intervention, including emergency operation. Computed tomography (CT) is essential for identifying cerebral hemorrhage, but its effectiveness is limited by the availability of experienced radiologists, especially in resource-constrained regions or when shorthanded during holidays or at night. Despite advancements in artificial intelligence–driven diagnostic tools, most require technical expertise. This poses a challenge for widespread adoption in radiological imaging. The introduction of advanced natural language processing (NLP) models such as GPT-4, which can annotate and analyze images without extensive algorithmic training, offers a potential solution. Objective This study investigates GPT-4’s capability to identify and annotate cerebral hemorrhages in cranial CT scans. It represents a novel application of NLP models in radiological imaging. Methods In this retrospective analysis, we collected 208 CT scans with 6 types of cerebral hemorrhages at Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, between January and September 2023. All CT images were mixed together and sequentially numbered, so each CT image had its own corresponding number. A random sequence from 1 to 208 was generated, and all CT images were inputted into GPT-4 for analysis in the order of the random sequence. The outputs were subsequently examined using Photoshop and evaluated by experienced radiologists on a 4-point scale to assess identification completeness, accuracy, and success. Results The overall identification completeness percentage for the 6 types of cerebral hemorrhages was 72.6% (SD 18.6%). Specifically, GPT-4 achieved higher identification completeness in epidural and intraparenchymal hemorrhages (89.0%, SD 19.1% and 86.9%, SD 17.7%, respectively), yet its identification completeness percentage in chronic subdural hemorrhages was very low (37.3%, SD 37.5%). The misidentification percentages for complex hemorrhages (54.0%, SD 28.0%), epidural hemorrhages (50.2%, SD 22.7%), and subarachnoid hemorrhages (50.5%, SD 29.2%) were relatively high, whereas they were relatively low for acute subdural hemorrhages (32.6%, SD 26.3%), chronic subdural hemorrhages (40.3%, SD 27.2%), and intraparenchymal hemorrhages (26.2%, SD 23.8%). The identification completeness percentages in both massive and minor bleeding showed no significant difference (P=.06). However, the misidentification percentage in recognizing massive bleeding was significantly lower than that for minor bleeding (P=.04). The identification completeness percentages and misidentification percentages for cerebral hemorrhages at different locations showed no significant differences (all P>.05). Lastly, radiologists showed relative acceptance regarding identification completeness (3.60, SD 0.54), accuracy (3.30, SD 0.65), and success (3.38, SD 0.64). Conclusions GPT-4, a standout among NLP models, exhibits both promising capabilities and certain limitations in the realm of radiological imaging, particularly when it comes to identifying cerebral hemorrhages in CT scans. This opens up new directions and insights for the future development of NLP models in radiology. Trial Registration ClinicalTrials.gov NCT06230419; https://clinicaltrials.gov/study/NCT06230419

In managing severe traumatic brain injury (TBI), emergency surgery involving the removal of damaged brain tissue and intracerebral hemorrhage is a priority. Secondary brain injury caused by oxidative stress and energy metabolic disorders, triggered by both primary mechanical brain damage and surgical insult, is also a determining factor in the prognosis of TBI. Unfortunately, the effectiveness of traditional postoperative intravenous neuroprotective agents therapy is often limited by the lack of targeting, timeliness, and side effects when neuroprotective agents systemically delivered. Here, we have developed injectable, intelligent, self-assembling hydrogels (P-RT/2DG) that can achieve precise treatment through intraoperative application to the target area. P-RT/2DG hydrogels were prepared by integrating a reactive oxygen species (ROS)-responsive thioketal linker (RT) into polyethylene glycol. By scavenging ROS and releasing 2-deoxyglucose (2DG) during degradation, these hydrogels functioned both in antioxidation and energy metabolism to inhibit the vicious cycle of post-TBI ROS-lactate which provoked secondary injury. In vitro and in vivo tests confirmed the absence of systemic side effects and the neuroprotective function of P-RT/2DG hydrogels in reducing edema, nerve cell apoptosis, neuroinflammation, and maintaining the blood-brain barrier. Our study thus provides a potential treatment strategy with novel hydrogels in TBI.

Lactates accumulation following traumatic brain injury (TBI) is detrimental. However, whether lactylation is triggered and involved in the deterioration of TBI remains unknown. Here, we first report that Tufm lactylation pathway induces neuronal apoptosis in TBI. Lactylation is found significantly increased in brain tissues from patients with TBI and mice with controlled cortical impact (CCI), and in neuronal injury cell models. Tufm, a key factor in mitophagy, is screened and identified to be mostly lactylated. Tufm is detected to be lactylated at K286 and the lactylation inhibits the interaction of Tufm and Tomm40 on mitochondria. The mitochondrial distribution of Tufm is then inhibited. Consequently, Tufm-mediated mitophagy is suppressed while mitochondria-induced neuronal apoptosis is increased. In contrast, the knockin of a lactylation-deficient TufmK286R mutant in mice rescues the mitochondrial distribution of Tufm and Tufm-mediated mitophagy, and improves functional outcome after CCI. Likewise, mild hypothermia, as a critical therapeutic method in neuroprotection, helps in downregulating Tufm lactylation, increasing Tufm-mediated mitophagy, mitigating neuronal apoptosis, and eventually ameliorating the outcome of TBI. A novel molecular mechanism in neuronal apoptosis, TBI-initiated Tufm lactylation suppressing mitophagy, is thus revealed.

IntroductionThe elderly population is more vulnerable to traumatic brain injury (TBI) compared with younger adults, and there is an increasing trend in TBI-related hospitalisations and deaths in the elderly due to the ageing global population. This is a thorough update to a previous meta-analysis on the mortality of elderly TBI patients. Our review will include more recent studies and provide a comprehensive analysis of risk factors.Methods and analysisThe protocol of our systematic review and meta-analysis is reported following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Protocols guidelines. We will search the following databases: PubMed, Cochrane Library and Embase from inception to 1 February 2023 reporting in-hospital mortality and/or risk factors predicting in-hospital mortality among elderly patients with TBI. We will perform a quantitative synthesis for in-hospital mortality data combined with meta-regression and subgroup analysis to determine whether there is a trend or source of heterogeneity. Pooled estimates for risk factors will be presented in the form of ORs and 95% CIs. Examples of risk factors include age, gender, cause of injury, severity of injury, neurosurgical intervention and preinjury antithrombotic therapy. Dose–response meta-analysis for age and risk of in-hospital mortality will be performed if sufficient studies are included. We will perform a narrative analysis if quantitative synthesis is not appropriate.Ethics and disseminationEthics approval is not required; we will publish findings from this study in a peer-reviewed journal and present results at national and international conferences. This study will promote a better understanding and management of elderly/geriatric TBI.PROSPERO registration numberCRD42022323231.

Protein therapeutics are anticipated to offer significant treatment options for central nervous system (CNS) diseases. However, the majority of proteins are unable to traverse the blood-brain barrier (BBB) and reach their CNS target sites. Inspired by the natural environment of active proteins, the cell matrix components hyaluronic acid (HA) and protamine (PRTM) are used to self-assemble with proteins to form a protein-loaded biomimetic core and then incorporated into ApoE3-reconstituted high-density lipoprotein (rHDL) to form a protein-loaded biomimetic nanocarrier (Protein-HA-PRTM-rHDL). This cell matrix-inspired biomimetic nanocarrier facilitates the penetration of protein therapeutics across the BBB and enables their access to intracellular target sites. Specifically, CAT-HA-PRTM-rHDL facilitates rapid intracellular delivery and release of catalase (CAT) via macropinocytosis-activated membrane fusion, resulting in improved spatial learning and memory in traumatic brain injury (TBI) model mice (significantly reduces the latency of TBI mice and doubles the number of crossing platforms), and enhances motor function and prolongs survival in amyotrophic lateral sclerosis (ALS) model mice (extended the median survival of ALS mice by more than 10 days). Collectively, this cell matrix-inspired nanoplatform enables the efficient CNS delivery of protein therapeutics and provides a novel approach for the treatment of CNS diseases.

Traumatic brain injury (TBI) is one of the leading public health concerns in the world. Therapeutic hypothermia is routinely used in severe TBI, and pathophysiological hyperthermia, frequently observed in TBI patients, has an unclear impact on drug transport in the injured brain due to a lack of study on its effects. We investigated the effect of post-traumatic therapeutic hypothermia at 33°C and pathophysiological hyperthermia at 39°C on brain transport and cell uptake of neuroprotectants after TBI. Recombinant high-density lipoprotein (rHDL), which possesses anti-inflammatory, antioxidant activity, and blood–brain barrier (BBB) permeability, was chosen as the model drug. First, we found that mild hypothermia and hyperthermia impaired rHDL transport to the brain and lesion targeting in controlled cortical impact mice. Second, we investigated the temperature-induced rHDL uptake shift by various brain cell types. Mild hypothermia impeded the uptake of rHDL by endothelial cells, neurons, microglia, and astrocytes. Hyperthermia impeded the uptake of rHDL by endothelial cells and neurons while promoting its uptake by microglia and astrocytes. In an attempt to understand the mechanisms behind the above phenomena, it was found that temperature induced brain-intake shift of rHDL through the regulation of low-density lipoprotein receptor (LDLR) and LDLR-related protein 1 (LRP1) stability in brain cells. We therefore reported the full view of the temperature-induced brain-intake shift of rHDL after TBI for the first time. It would be of help in coordinating pharmacotherapy with temperature management in individualization and precision medicine.

Prognostic prediction of traumatic brain injury (TBI) in patients is crucial in clinical decision and health care policy making. This study aimed to develop and validate prediction models for in-hospital mortality after severe traumatic brain injury (sTBI). We developed and validated logistic regression (LR), LASSO regression, and machine learning (ML) algorithms including support vector machines (SVM) and XGBoost models. Fifty-four candidate predictors were included. Model performance was expressed in terms of discrimination (C-statistic) and calibration (intercept and slope). For model development, 2804 patients with sTBI in the Collaborative European NeuroTrauma Effectiveness Research in TBI (CENTER-TBI) China Registry study were included. External validation was performed in 1113 patients with sTBI in the CENTER-TBI European Registry study. XGBoost achieved high discrimination in mortality prediction, and it outperformed logistic and LASSO regression. The XGBoost model established in this study also outperformed prediction models currently available, including the International Mission for Prognosis and Analysis of Clinical Trials (IMPACT) core and International Mission for Prognosis and Analysis of Clinical Trials (CRASH) basic models. When including 54 variables, XGBoost and SVM reached C-statistics of 0.87 (95% confidence interval [CI]: 0.81-0.92) and 0.85 (95% CI: 0.79-0.90) at internal validation, and 0.88 (95% CI: 0.87-0.88) and 0.86 (95% CI: 0.85-0.87) at external validation, respectively. A simplified version of XGBoost and SVM using 26 variables selected by recursive feature elimination (RFE) reached C-statistics of 0.87 (95% CI: 0.82-0.92) and 0.86 (95% CI: 0.80-0.91) at internal validation, and 0.87 (95% CI: 0.87-0.88) and 0.87 (95% CI: 0.86-0.87) at external validation, respectively. However, when the number of variables included decreased, the difference between ML and LR diminished. All the prediction models can be accessed via a web-based calculator. Glasgow Coma Scale (GCS) score, age, pupillary light reflex, Injury Severity Score (ISS) for brain region, and the presence of acute subdural hematoma were the five strongest predictors for mortality prediction. The study showed that ML techniques such as XGBoost may capture information hidden in demographic and clinical predictors of patients with sTBI and yield more precise predictions compared with LR approaches.

The condition of patients with severe traumatic brain injury (sTBI) complicated by corona virus 2019 disease (COVID-19) is complex. sTBI can significantly increase the probability of COVID-19 developing into severe or critical stage, while COVID-19 can also increase the surgical risk of sTBI and the severity of postoperative lung lesions. There are many contradictions in the treatment process, which brings difficulties to the clinical treatment of such patients. Up to now, there are few clinical studies and therapeutic norms relevant to sTBI complicated by COVID-19. In order to standardize the clinical treatment of such patients, Critical Care Medicine Branch of China International Exchange and Promotive Association for Medical and Healthcare and Editorial Board of Chinese Journal of Trauma organized relevant experts to formulate the Chinese expert consensus on clinical treatment of adult patients with severe traumatic brain injury complicated by corona virus infection 2019 ( version 2023) based on the joint prevention and control mechanism scheme of the State Council and domestic and foreign literatures on sTBI and COVID-19 in the past 3 years of the international epidemic. Fifteen recommendations focused on emergency treatment, emergency surgery and comprehensive management were put forward to provide a guidance for the diagnosis and treatment of sTBI complicated by COVID-19.

Severe traumatic brain injury (TBI) leads to acute coma and may result in prolonged disorder of consciousness (pDOC). We aimed to determine whether right median nerve electrical stimulation is a safe and effective treatment for accelerating emergence from coma after TBI. This randomised controlled trial was performed in 22 centres in China. Participants with acute coma at 7–14 days after TBI were randomly assigned (1:1) to either routine therapy and right median nerve electrical stimulation (RMNS group) or routine treatment (control group). The RMNS group received 20 mA, 300 μs, 40 Hz stimulation pulses, lasting 20 s per minutes, 8 h per day, for 2 weeks. The primary outcome was the proportion of patients who regained consciousness 6 months post-injury. The secondary endpoints were Glasgow Coma Scale (GCS), Full Outline of Unresponsiveness scale (FOUR), Coma Recovery Scale-Revised (CRS-R), Disability Rating Scale (DRS) and Glasgow Outcome Scale Extended (GOSE) scores reported as medians on day 28, 3 months and 6 months after injury, and GCS and FOUR scores on day 1 and day 7 during stimulation. Primary analyses were based on the intention-to-treat set. Between March 26, 2016, and October 18, 2020, 329 participants were recruited, of whom 167 were randomised to the RMNS group and 162 to the control group. At 6 months post-injury, a higher proportion of patients in the RMNS group regained consciousness compared with the control group (72.5

Traumatic brain injury (TBI) leads to neuropsychiatric symptoms and increased risk of neurodegenerative disorders. Mild hypothermia is commonly used in patients suffering from severe TBI. However, its effect for long-term protection is limited, mostly because of its insufficient anti-inflammatory and neuroprotective efficacy and restricted treatment duration. Recombinant high-density lipoprotein (rHDL), which possesses anti-inflammatory and antioxidant activity and blood-brain barrier (BBB) permeability, was expected to potentially strengthen the therapeutic effect of mild hypothermia in TBI treatment. To test this hypothesis and optimize the regimen for combination therapy, the efficacy of mild hypothermia plus concurrent or sequential rHDL on oxidative stress, inflammatory reaction, and cell survival in the damaged brain cells was evaluated. It was found that the effect of combining mild hypothermia with concurrent rHDL was modest, as mild hypothermia inhibited the cellular uptake and lesion-site-targeting delivery of rHDL. In contrast, the combination of mild hypothermia with sequential rHDL more powerfully improved the anti-inflammatory and antioxidant activities, promoted nerve cell survival and BBB restoration, and ameliorated neurologic changes, which thus remarkably restored the spatial learning and memory ability of TBI mice. Collectively, these findings suggest that rHDL may serve as a novel nanomedicine for adjunctive therapy of TBI and highlight the importance of timing of combination therapy for optimal treatment outcome.