Lyophilizable Stem Cell-Hybrid Liposome with Long-Term Stability and High Targeting Capacity.

The hybridization of liposome with stem cell membrane is an emerging technology to prepare the nanovehicle with the capacity of disease-responsive targeting. However, the long-term storage of this hybrid liposome has received limited attention in the literature, which is essential for their potential applicability in the clinic. Therefore, the preservation of long-term activity of stem cell-hybrid liposome using freeze-drying is investigated in the present study. Mesenchymal stem cell-hybrid liposome is synthesized and its feasibility for freeze-drying under different conditions is examined. Results revealed that pre-freezing the hybrid liposome at -20 °C in Tris buffer solution (pH 7.4) containing 10% trehalose could well preserve the liposomal structure for at least 3 months. Notably, major membrane proteins on the hybrid liposome are protected in this formulation and CXCR4-associated targeting capacity is maintained both in vitro and in vivo. Consequently, the hybrid liposome stored for 3 months demonstrate a comparable tumor inhibition as the fresh-prepared ones. The present study provides the first insights into the long-term storage of stem cell hybrid liposome using lyophilization, which may make an important step forward in enhancing the long-term stability of these promising biomimetic nanovehicle and ease the logistics and the freeze-storage in the potential clinical applications. This article is protected by copyright. All rights reserved.

Strategy for Identifying a Robust Metabolomic Signature Reveals the Altered Lipid Metabolism in Pituitary Adenoma.

Despite the well-established connection between systematic metabolic abnormalities and the pathophysiology of pituitary adenoma (PA), current metabolomic studies have reported an extremely limited number of metabolites associated with PA. Moreover, there was very little consistency in the identified metabolite signatures, resulting in a lack of robust metabolic biomarkers for the diagnosis and treatment of PA. Herein, we performed a global untargeted plasma metabolomic profiling on PA and identified a highly robust metabolomic signature based on a strategy. Specifically, this strategy is unique in (1) integrating repeated random sampling and a consensus evaluation-based feature selection algorithm and (2) evaluating the consistency of metabolomic signatures among different sample groups. This strategy demonstrated superior robustness and stronger discriminative ability compared with that of other feature selection methods including Student's t-test, partial least-squares-discriminant analysis, support vector machine recursive feature elimination, and random forest recursive feature elimination. More importantly, a highly robust metabolomic signature comprising 45 PA-specific differential metabolites was identified. Moreover, metabolite set enrichment analysis of these potential metabolic biomarkers revealed altered lipid metabolism in PA. In conclusion, our findings contribute to a better understanding of the metabolic changes in PA and may have implications for the development of diagnostic and therapeutic approaches targeting lipid metabolism in PA. We believe that the proposed strategy serves as a valuable tool for screening robust, discriminating metabolic features in the field of metabolomics.

A Pluripotential Neutrophil-Mimic Nanovehicle Modulates Immune Microenvironment with Targeted Drug Delivery for Augmented Antitumor Chemotherapy.

The limited therapeutic outcomes and severe systemic toxicity of chemotherapy remain major challenges to the current clinical antitumor therapeutic regimen. Tumor-targeted drug delivery that diminishes the undifferentiated systemic distribution is a practical solution to ameliorating systemic toxicity. However, the tumor adaptive immune microenvironment still poses a great threat that compromises the therapeutic efficacy of chemotherapy by promoting the tolerance of the tumor cells. Herein, a pluripotential neutrophil-mimic nanovehicle (Neutrosome(L)) composed of an activated neutrophil membrane-incorporated liposome is proposed to modulate the immune microenvironment and synergize antitumor chemotherapy. The prominent tumor targeting capability inherited from activated neutrophils and the improved tumor penetration ability of Neutrosome(L) enable considerable drug accumulation in tumor tissues (more than sixfold that of free drug). Importantly, Neutrosome(L) can modulate the immune microenvironment by restricting neutrophil infiltration in tumor tissue, which may be attributed to the neutralization of inflammatory cytokines, thus potentiating antitumor chemotherapy. As a consequence, the treatment of cisplatin-loaded Neutrosome(L) performs prominent tumor suppression effects, reduces systemic drug toxicity, and prolongs the survival period of tumor-bearing mice. The pluripotential neutrophil-mimic nanovehicle proposed in this study can not only enhance the tumor accumulation of chemotherapeutics but also modulate the immune microenvironment, providing a compendious strategy for augmented antitumor chemotherapy.

A large-scale production of mesenchymal stem cells and their exosomes for an efficient treatment against lung inflammation.

Mesenchymal stem cells (MSCs) and their produced exosomes have demonstrated inherent capabilities of inflammation-guided targeting and inflammatory modulation, inspiring their potential applications as biologic agents for inflammatory treatments. However, the clinical applications of stem cell therapies are currently restricted by several challenges, and one of them is the mass production of stem cells to satisfy the therapeutic demands in the clinical bench. Herein, a production of human amnion-derived MSCs (hMSCs) at a scale of over 1 × 109 cells per batch was reported using a three-dimensional (3D) culture technology based on microcarriers coupled with a spinner bioreactor system. The present study revealed that this large-scale production technology improved the inflammation-guided migration and the inflammatory suppression of hMSCs, without altering their major properties as stem cells. Moreover, these large-scale produced hMSCs showed an efficient treatment against the lipopolysaccharide (LPS)-induced lung inflammation in mice models. Notably, exosomes collected from these large-scale produced hMSCs were observed to inherit the efficient inflammatory suppression capability of hMSCs. The present study showed that 3D culture technology using microcarriers coupled with a spinner bioreactor system can be a promising strategy for the large-scale expansion of hMSCs with improved anti-inflammation capability, as well as their secreted exosomes.

Targeting cancer-associated fibroblast autophagy renders pancreatic cancer eradicable with immunochemotherapy by inhibiting adaptive immune resistance.

Accumulating evidence suggests that cancer-associated fibroblast (CAF) macroautophagy/autophagy is crucial in tumor development and may be a therapeutic target for pancreatic ductal adenocarcinoma (PDAC). However, the role of CAF autophagy during immune surveillance and cancer immunotherapy is unclear. The present study revealed that the inhibition of CAF autophagy suppresses in vivo tumor development in immune-deficient xenografts. This deletion compromises anti-tumor immunity and anti-tumor efficacy both in vitro and in vivo by upregulating CD274/PDL1 levels in an immune-competent mouse model. A block in CAF autophagy reduced the production of IL6 (interleukin 6), disrupting high desmoplastic TME and decreasing USP14 expression at the transcription level in pancreatic cancer cells. We further identify USP14 as the post-translational factor responsible for downregulating CD274 expression by removing K63 linked-ubiquitination at the K280 residue. Finally, chloroquine diphosphate-loaded mesenchymal stem cell (MSC)-liposomes, by accurately targeting CAFs, inhibited CAF autophagy, improving the efficacy of immunochemotherapy to combat pancreatic cancer.Abbreviation: AIR: adaptive immune resistance; ATRA: all-trans-retinoicacid; CAF: cancer-associated fibroblast; CD274/PDL1: CD274 molecule; CM: conditioned medium; CQ: chloroquine diphosphate; CyTOF: Mass cytometry; FGF2/bFGF: fibroblast growth factor 2; ICB: immune checkpoint blockade; IF: immunofluorescence; IHC: immunohistochemistry; IP: immunoprecipitation; MS: mass spectrometer; MSC: mesenchymal stem cell; PDAC: pancreatic ductal adenocarcinoma; TEM: transmission electron microscopy; TILs: tumor infiltrating lymphocytes; TME: tumor microenvironment; USP14: ubiquitin specific peptidase 14.

Initial IL-10 production dominates the therapy of mesenchymal stem cell scaffold in spinal cord injury.

Rationale: Spinal cord injury (SCI) is an acute damage to the central nervous system that results in severe morbidity and permanent disability. Locally implanted scaffold systems with immobilized mesenchymal stem cells (MSCs) have been widely proven to promote locomotor function recovery in SCI rats; however, the underlying mechanism remains elusive. Methods and Results: In this study, we constructed a hyaluronic acid scaffold system (HA-MSC) to accelerate the adhesive growth of human MSCs and prolong their survival time in SCI rat lesions. MSCs regulate local immune responses by upregulating the expression of anti-inflammatory cytokines. Interestingly, the dramatically increased, but transient expression of interleukin 10 (IL-10) is found to be secreted by MSCs in the first week. Blocking the function of the initially produced IL-10 by the antibody completely abolished the neurological and behavioral recovery of SCI rats, indicating a core role of IL-10 in SCI therapy with HA-MSC implantation. Transcriptome analyses indicated that IL-10 selectively promotes the migration and cytokine secretion-associated programs of MSCs, which in turn helps MSCs exert their anti-inflammatory therapeutic effects. Conclusion: Our findings highlight a novel role of IL-10 in regulating MSC migration and cytokine secretion-associated programs, and determine the vital role of IL-10 in the domination of MSC treatment for spinal cord repair.

TheMarker: a comprehensive database of therapeutic biomarkers.

Distinct from the traditional diagnostic/prognostic biomarker (adopted as the indicator of disease state/process), the therapeutic biomarker (ThMAR) has emerged to be very crucial in the clinical development and clinical practice of all therapies. There are five types of ThMAR that have been found to play indispensable roles in various stages of drug discovery, such as: Pharmacodynamic Biomarker essential for guaranteeing the pharmacological effects of a therapy, Safety Biomarker critical for assessing the extent or likelihood of therapy-induced toxicity, Monitoring Biomarker indispensable for guiding clinical management by serially measuring patients' status, Predictive Biomarker crucial for maximizing the clinical outcome of a therapy for specific individuals, and Surrogate Endpoint fundamental for accelerating the approval of a therapy. However, these data of ThMARs has not been comprehensively described by any of the existing databases. Herein, a database, named 'TheMarker', was therefore constructed to (a) systematically offer all five types of ThMAR used at different stages of drug development, (b) comprehensively describe ThMAR information for the largest number of drugs among available databases, (c) extensively cover the widest disease classes by not just focusing on anticancer therapies. These data in TheMarker are expected to have great implication and significant impact on drug discovery and clinical practice, and it is freely accessible without any login requirement at: https://idrblab.org/themarker.

Single-cell characterization of deformation and dynamics of mesenchymal stem cells in microfluidic systems: A computational study.

Understanding the homing dynamics of individual mesenchymal stem cells (MSCs) in physiologically relevant microenvironments is crucial for improving the efficacy of MSC-based therapies for therapeutic and targeting purposes. This study investigates the passive homing behavior of individual MSCs in micropores that mimic interendothelial clefts through predictive computational simulations informed by previous microfluidic experiments. Initially, we quantified the size-dependent behavior of MSCs in micropores and elucidated the underlying mechanisms. Subsequently, we analyzed the shape deformation and traversal dynamics of each MSC. In addition, we conducted a systematic investigation to understand how the mechanical properties of MSCs impact their traversal process. We considered geometric and mechanical parameters, such as reduced cell volume, cell-to-nucleus diameter ratio, and cytoskeletal prestress states. Furthermore, we quantified the changes in the MSC traversal process and identified the quantitative limits in their response to variations in micropore length. Taken together, the computational results indicate the complex dynamic behavior of individual MSCs in the confined microflow. This finding offers an objective way to evaluate the homing ability of MSCs in an interendothelial-slit-like microenvironment.

Risk of deep vein thrombosis (DVT) in lower extremity after total knee arthroplasty (TKA) in patients over 60 years old.

PURPOSE: There is a significant risk of DVT after TKA. We aim to evaluate the potential risk factors for postoperative DVT in the lower extremities in TKA patients over 60 years of age and provide a reference for the effective prevention of DVT. METHODS: This retrospective study included patients older than 60 who underwent TKA surgery in our hospital from May 2015 to May 2022 and compared and analyzed patients' personal characteristics and clinical data with or without postoperative DVT. Logistic regression analysis was performed to determine the potential risk factors for DVT after TKA. The sensitivity and specificity of each risk factor in the diagnosis of DVT were compared by the ROC curve, and the value of this model in the diagnosis of DVT was further investigated using a multivariable combined diagnosis ROC curve model. RESULTS: A total of 661 patients over 60 who underwent TKA were included. Preoperative Hematocrit (HCT), platelet count, anesthesia mode, postoperative D-dimer, ESR, diabetes mellitus, and other aspects of the DVT group and non-DVT group were statistically significant after TKA (P < 0.05). Multivariate logistics regression analysis showed that preoperative HCT, anesthesia mode, and diabetes were independent risk factors for DVT in patients over 60 years old after TKA. Compared with the univariate ROC model, the multivariable combined ROC curve analysis model has a higher diagnostic value for the diagnosis of DVT. CONCLUSION: DVT is common in patients over 60 years of age after TKA, and there is a multivariable influence on its pathogenesis. For patients over 60 with diabetes, neuraxial anesthesia is recommended for patients with high preoperative HCT levels, which may reduce the incidence of postoperative DVT.

Multifunctional Nanoassembly for MRI-Trackable Dendritic Cell Dependent and Independent Photoimmunotherapy.

Immunotherapy has emerged as a triumph in the treatment of malignant cancers. Nevertheless, current immunotherapeutics are insufficient in addressing tumors characterized by tumor cells' inadequate antigenicity and the tumor microenvironment's low immunogenicity (TME). Herein, we developed a novel multifunctional nanoassembly termed FMMC through the self-assembly of indoleamine 2,3-dioxygenase 1 (IDO-1) inhibitor 1-methyl-tryptophan prodrug (FM), Ce6, and ionic manganese (Mn2+) via noncovalent interactions. The laser-ignited FMMC treatment could induce effective immunogenic cell death and activate the STING/MHC-I signaling pathway, thus deeply sculpting the tumor-intrinsic antigenicity to achieve dendritic cell (DC)-dependent and -independent T cell responses against tumors. Meanwhile, by inhibiting IDO-1, FMMC could lead to immunosuppressive TME reversion to an immunoactivated one. FMMC-based phototherapy led to the up-regulation of programmed death-ligand 1 (PD-L1), enhancing the sensitivity of tumors to anti-PD-1 therapy. Furthermore, the incorporation of Mn2+ into FMMC resulted in an augmented longitudinal relaxivity and enhanced the MRI for monitoring the growth of primary tumors and lung metastases. Collectively, the superior reprogramming performance of immunosuppressive tumor cells and TME, combined with excellent anticancer efficacy and MRI capability, made FMMC a promising immune nanosculptor for cancer theranostics.

Efficient intervention for pulmonary fibrosis via mitochondrial transfer promoted by mitochondrial biogenesis.

The use of exogenous mitochondria to replenish damaged mitochondria has been proposed as a strategy for the treatment of pulmonary fibrosis. However, the success of this strategy is partially restricted by the difficulty of supplying sufficient mitochondria to diseased cells. Herein, we report the generation of high-powered mesenchymal stem cells with promoted mitochondrial biogenesis and facilitated mitochondrial transfer to injured lung cells by the sequential treatment of pioglitazone and iron oxide nanoparticles. This highly efficient mitochondrial transfer is shown to not only restore mitochondrial homeostasis but also reactivate inhibited mitophagy, consequently recovering impaired cellular functions. We perform studies in mouse to show that these high-powered mesenchymal stem cells successfully mitigate fibrotic progression in a progressive fibrosis model, which was further verified in a humanized multicellular lung spheroid model. The present findings provide a potential strategy to overcome the current limitations in mitochondrial replenishment therapy, thereby promoting therapeutic applications for fibrotic intervention.

Inorganic nanoparticle-integrated mesenchymal stem cells: A potential biological agent for multifaceted applications.

Mesenchymal stem cell (MSC)-based therapies are flourishing. MSCs could be used as potential therapeutic agents for regenerative medicine due to their own repair function. Meanwhile, the natural predisposition toward inflammation or injury sites makes them promising carriers for targeted drug delivery. Inorganic nanoparticles (INPs) are greatly favored for their unique properties and potential applications in biomedical fields. Current research has integrated INPs with MSCs to enhance their regenerative or antitumor functions. This model also allows the in vivo fate tracking of MSCs in multiple imaging modalities, as many INPs are also excellent contrast agents. Thus, INP-integrated MSCs would be a multifunctional biologic agent with great potential. In this review, the current roles performed by the integration of INPs with MSCs, including (i) enhancing their repair and regeneration capacity via the improvement of migration, survival, paracrine, or differentiation properties, (ii) empowering tumor-killing ability through agent loaded or hyperthermia, and (iii) conferring traceability are summarized. An introduction of INP-integrated MSCs for simultaneous treatment and tracking is also included. The promising applications of INP-integrated MSCs in future treatments are emphasized and the challenges to their clinical translation are discussed.

The value of FT4/TSH ratio in the differential diagnosis of Graves' disease and subacute thyroiditis.

Objective: To explore the value of the FT4/TSH ratio in the etiological diagnosis of newly diagnosed patients with thyrotoxicosis. Methods: The retrospective study was conducted on 287 patients with thyrotoxicosis (122 patients with subacute thyroiditis and 165 patients with Graves' disease) and 415 healthy people on their first visit to our hospital. All patients underwent thyroid function tests including the measurement of T3, T4, FT3, FT4, TSH, T3/TSH, and T4/TSH. The receiver operating characteristic (ROC) curve was employed to evaluate the value of FT4/TSH in the differential diagnosis of Graves' disease and subacute thyroiditis, and compared with other related indicators. Results: The area under the curve of FT4/TSH for diagnosing Graves' disease and thyroiditis was 0.846, which was significantly larger than the area under the curve of T3/T4 ratio (P< 0.05) and FT3/FT4 ratio (P< 0.05). When the cut-off value of the FT4/TSH ratio was 5731.286 pmol/mIU, the sensitivity was 71.52%, the specificity was 90.16%, the positive predictive value was 90.77% and the negative predictive value was 70.06%. The diagnostic accuracy was 79.44%. Conclusion: FT4/TSH ratio can be used as a new reference index for the differential diagnosis of thyrotoxicosis.

Apoptotic Vesicles of MSCs: The Natural Therapeutic Agents and Bio-Vehicles for Targeting Drug Delivery.

Mesenchymal stem cell (MSC)-based therapies are increasingly recognized as promising cellular therapeutics and show the ability to treat various diseases. However, the underlying mechanism is not fully elucidated. Some recent studies have shown an unexpected result whereby MSCs undergo rapid apoptosis following administration but still exert therapeutic effects in some disease treatments. Such a therapeutic mechanism is believed to associate with the released apoptotic vesicles from apoptotic MSCs (MSC-ApoVs). This finding inspires a novel therapeutic strategy for using MSC-ApoVs for disease treatment. The present review aims to summarize the biogenesis, physiological functions, therapeutic potentials, and related mechanisms of apoptotic vesicles in MSC-based therapy. In addition, the potential applications of MSC-ApoVs as natural therapeutic agents and natural drug delivery vehicles are proposed and highlighted. The present review is hoped to provide a general understanding of MSC-ApoVs in disease treatment and inspire potential applications in targeted drug delivery.

Nanozyme-Integrated Thermoresponsive In Situ Forming Hydrogel Enhances Mesenchymal Stem Cell Viability and Paracrine Effect for Efficient Spinal Cord Repair.

Mesenchymal stem cell (MSC)-based therapy has emerged as a promising strategy for the treatment of spinal cord injury (SCI). However, the hostile microenvironment of SCI, which can adversely affect the survival and paracrine effect of the implanted MSCs, severely limits the therapeutic efficacy of this approach. Here, we report on a ceria nanozyme-integrated thermoresponsive in situ forming hydrogel (CeNZ-gel) that can enable dual enhancement of MSC viability and paracrine effect, leading to highly efficient spinal cord repair. The sol-gel transition property of the CeNZ-gel at body temperature ensures uniform coverage of the hydrogel in injured spinal cord tissues. Our results demonstrate that the CeNZ-gel significantly increases the viability of transplanted MSCs in the microenvironment by attenuating oxidative stress and, more importantly, promotes the secretion of angiogenic factors from MSCs by inducing autophagy of MSCs. The synergy between the oxidative stress-relieving effect of CeNZs and the paracrine effect of MSCs accelerates angiogenesis, nerve repair, and motor function recovery after SCI, providing an efficient strategy for MSC-based SCI therapy.

Cell membrane-based biomimetic vehicles for effective central nervous system target delivery: Insights and challenges.

Central nervous system (CNS) disorders, including brain tumor, ischemic stroke, Alzheimer's disease, and Parkinson's disease, threaten human health. And the existence of the blood-brain barrier (BBB) hinders the delivery of drugs and the design of drug targeting delivery vehicles. Over the past decades, great interest has been given to cell membrane-based biomimetic vehicles since the rise of targeting drug delivery systems and biomimetic nanotechnology. Cell membranes are regarded as natural multifunction biomaterials, and provide potential for targeting delivery design and modification. Cell membrane-based biomimetic vehicles appear timely with the participation of cell membranes and nanoparticles, and raises new lights for BBB recognition and transport, and effective therapy with its biological multifunction and high biocompatibility. This review summarizes existing challenges in CNS target delivery and recent advances of different kinds of cell membrane-based biomimetic vehicles for effective CNS target delivery, and deliberates the BBB targeting mechanism. It also discusses the challenges and possibility of clinical translation, and presents new insights for development.

Exosome-Based Regimen Rescues Endometrial Fibrosis in Intrauterine Adhesions Via Targeting Clinical Fibrosis Biomarkers.

Intrauterine adhesions (IUA), which is characterized by endometrial fibrosis, continue to be the most common cause of uterine infertility globally. Our work revealed that 3 fibrotic progression markers (Vimentin, COL5A2, and COL1A1) were significantly increased in the endometrium of IUA patients. Mesenchymal stem cell-derived exosomes (EXOs) have been recently revealed as a cell-free therapy for fibrosis diseases. Nevertheless, the application of EXOs is restricted by the short residency duration in the target tissue. To overcome this limitation, herein, we reported an exosome-based regimen (EXOs-HP) that thermosensitive poloxamer hydrogel possessed the ability to efficiently promote the residency duration of EXOs in the uterine cavity. By downregulating fibrotic progression markers (Vimentin, COL5A2, and COL1A1), EXOs-HP could significantly restore the function and structure of the injured endometrium in the IUA model. Our work provides the theoretical and experimental foundation of EXOs-HP in treating IUA, highlighting the clinical potential of topical EXOs-HP delivery system in IUA patients.

Bioresponsive Immunotherapeutic Materials.

The human immune system is an interaction network of biological processes, and its dysfunction is closely associated with a wide array of diseases, such as cancer, infectious diseases, tissue damage, and autoimmune diseases. Manipulation of the immune response network in a desired and controlled fashion has been regarded as a promising strategy for maximizing immunotherapeutic efficacy and minimizing side effects. Integration of "smart" bioresponsive materials with immunoactive agents including small molecules, biomacromolecules, and cells can achieve on-demand release of agents at targeted sites to reduce overdose-related toxicity and alleviate off-target effects. This review highlights the design principles of bioresponsive immunotherapeutic materials and discusses the critical roles of controlled release of immunoactive agents from bioresponsive materials in recruiting, housing, and manipulating immune cells for evoking desired immune responses. Challenges and future directions from the perspective of clinical translation are also discussed.

Cell membrane-coated nanoparticles: a novel multifunctional biomimetic drug delivery system.

Recently, nanoparticle-based drug delivery systems have been widely used for the treatment, prevention, and detection of diseases. Improving the targeted delivery ability of nanoparticles has emerged as a critical issue that must be addressed as soon as possible. The bionic cell membrane coating technology has become a novel concept for the design of nanoparticles. The diverse biological roles of cell membrane surface proteins endow nanoparticles with several functions, such as immune escape, long circulation time, and targeted delivery; therefore, these proteins are being extensively studied in the fields of drug delivery, detoxification, and cancer treatment. Furthermore, hybrid cell membrane-coated nanoparticles enhance the beneficial effects of monotypic cell membranes, resulting in multifunctional and efficient delivery carriers. This review focuses on the synthesis, development, and application of the cell membrane coating technology and discusses the function and mechanism of monotypic/hybrid cell membrane-modified nanoparticles in detail. Moreover, it summarizes the applications of cell membranes from different sources and discusses the challenges that may be faced during the clinical application of bionic carriers, including their production, mechanism, and quality control. We hope this review will attract more scholars toward bionic cell membrane carriers and provide certain ideas and directions for solving the existing problems.

Advanced Therapies for Traumatic Central Nervous System Injury: Delivery Strategy Reinforced Efficient Microglial Manipulation.

Traumatic central nervous system (CNS) injuries, including spinal cord injury and traumatic brain injury, are challenging enemies of human health. Microglia, the main component of the innate immune system in CNS, can be activated postinjury and are key participants in the pathological procedure and development of CNS trauma. Activated microglia can be typically classified into pro-inflammatory (M1) and anti-inflammatory (M2) phenotypes. Reducing M1 polarization while promoting M2 polarization is thought to be promising for CNS injury treatment. However, obstacles such as the low permeability of the blood-brain barrier and short retention time in circulation limit the therapeutic outcomes of administrated drugs, and rational delivery strategies are necessary for efficient microglial regulation. To this end, proper administration methods and delivery systems like nano/microcarriers and scaffolds are investigated to augment the therapeutic effects of drugs, while some of these delivery systems have self-efficacies in microglial manipulation. Besides, systems based on cell and cell-derived exosomes also show impressive effects, and some underlying targeting mechanisms of these delivery systems have been discovered. In this review, we introduce the roles of microglia play in traumatic CNS injuries, discuss the potential targets for the polarization regulation of microglial phenotype, and summarize recent studies and clinical trials about delivery strategies on enhancing the effect of microglial regulation and therapeutic outcome, as well as targeting mechanisms post CNS trauma.