Matrix Metalloproteinase-Responsive Drug Delivery Systems.

Matrix metalloproteinases (MMPs) are a class of endopeptidases that are dependent on zinc and facilitate the degradation of extracellular matrix (ECM) proteins, thereby playing pivotal parts in human physiology and pathology. MMPs regulate normal tissue and cellular functions, including tissue development, remodeling, angiogenesis, bone formation, and wound healing. Several diseases, including cancer, inflammation, cardiovascular diseases, and nervous system disorders, have been linked to dysregulated expression of specific MMP subtypes, which can promote tumor progression, metastasis, and inflammation. Various MMP-responsive drug delivery and release systems have been developed by harnessing cleavage activities and overexpression of MMPs in affected regions. Herein, we review the structure, substrates, and physiological and pathological functions of various MMPs and highlight the strategies for designing MMP-responsive nanoparticles to improve the targeting efficiency, penetration, and protection of therapeutic payloads.

Vitality-Enhanced Dual-Modal Tracking System Reveals the Dynamic Fate of Mesenchymal Stem Cells for Stroke Therapy.

Mesenchymal stem cell (MSC) therapy via intravenous transplantation exhibits great potential for brain tissue regeneration, but still faces thorny clinical translation challenges as the unknown dynamic fate leads to the contentious therapeutic mechanism and the poor MSC viability in harsh lesions limits therapeutic efficiency. Here, a vitality-enhanced dual-modal tracking system is designed to improve engraftment efficiency and is utilized to noninvasively explore the fate of intravenous transplanted human umbilical cord-derived MSCs during long-term treatment of ischemic stroke. Such a system is obtained by bioorthogonally conjugating magnetic resonance imaging (MRI) contrast and near-infrared fluorescence (NIRF) imaging nanoparticles to metabolic glycoengineered MSCs with a lipoic acid-containing extracellular antioxidative protective layer. The dynamic fates of MSCs in multi-dimensional space-time evolution are digitally detailed for up to 28 days using MRI and NIRF imaging equipment, and the protective layer greatly shields MSCs from reactive oxygen spices (ROS) degradation, enhances MSC survival, and engraftment efficiency. Additionally, it is observed that the bioengineered MSCs exhibit dynamic intelligent responses corresponding to microenvironment remodeling and exert enhanced therapeutic effects. This dual-modal tracking system enables long-term tracking of MSCs while improving their viability at the lesion sites, which may serve as a valuable tool for expediting the clinical translation of MSC therapy.

Bullet screen in pre-clinical undergraduate pharmacology education: a survey study.

BACKGROUND: The lack of interaction and communication in pharmacology courses, especially since the onset of the coronavirus disease 2019 (COVID-19) pandemic, which required a fast shift to remote learning at medical schools, leads to an unsatisfactory learning outcome. New interactive teaching approaches are required to improve pharmacology learning attention and interaction in remote education and traditional classrooms. METHODS: We introduced bullet screens to pharmacology teaching. Then, a survey was distributed to first-, second- and third-year pre-clinical undergraduate medical and nursing students at the Shanghai Jiao Tong University School of Medicine from November 2020 to March 2022. We evaluated the essential features, instructional effectiveness, and entertainment value of bullet screens. Responses to structured and open-ended questions about the strengths and weaknesses of the bullet screen and overall thoughts were coded and compared between medical and nursing students. RESULTS: In terms of essential features, bullet screens have a high degree of acceptability among students, and this novel instructional style conveniently increased classroom interaction. Considering instructional effectiveness, bullet screen may stimulate students' in-depth thinking. Meanwhile, students tended to use bullet-screen comments as a way to express their support rather than to make additional comments or to express their different viewpoints. The entertainment value of bullet screen was noteworthy. The lack of ideas might lead to relative differences between medical and nursing students, indicating that guiding the appropriate use of bullet screen is necessary. CONCLUSIONS: The bullet screen may be popularized as an auxiliary teaching approach to promote interaction between teachers and students in the classroom as well as during remote education. It is an interesting and beneficial tool in pharmacology courses, yet there are several aspects of this device that should be improved for popularization.

Tailored Chemodynamic Nanomedicine Improves Pancreatic Cancer Treatment via Controllable Damaging Neoplastic Cells and Reprogramming Tumor Microenvironment.

Pancreatic ductal adenocarcinoma (PDAC) strongly resists standard therapies since KRAS-mutated cancer cells harbor endogenous resistance toward chemotherapy-induced apoptosis and tumor-associated macrophages (TAMs) activate stroma cells to create the nearly impenetrable matrix. Herein, we developed a tailored nanocomplex through the self-assembly of synthetic 4-(phosphonooxy)phenyl-2,4-dinitrobenzenesulfonate and Fe3+ followed by hyaluronic acid decoration, realizing chemodynamic therapy (CDT) to combat PDAC. By controllably releasing its components in a GSH-sensitive manner under the distinctive redox homeostasis in cancer cells and TAMs, the nanocomplex selectively triggered a Fenton reaction to induce oxidative damage in cancer cells and simultaneously repolarized TAMs to deactivate stromal cells and thus attenuate stroma. Compared to gemcitabine, CDT remarkably inhibited tumor growth and prolonged animal survival in orthotopic PDAC models without noticeable side effects. This study provides a promising strategy to improve the treatment of PDAC through CDT-mediated controlled cancer cells damage and reprogramming of the stromal microenvironment.

Sequential Targeting TGF-ß Signaling and KRAS Mutation Increases Therapeutic Efficacy in Pancreatic Cancer.

Pancreatic cancer is a highly aggressive malignancy that strongly resists extant treatments. The failure of existing therapies is majorly attributed to the tough tumor microenvironment (TME) limiting drug access and the undruggable targets of tumor cells. The formation of suppressive TME is regulated by transforming growth factor beta (TGF-ß) signaling, while the poor response and short survival of almost 90% of pancreatic cancer patients results from the oncogenic KRAS mutation. Hence, simultaneously targeting both the TGF-ß and KRAS pathways might dismantle the obstacles of pancreatic cancer therapy. Here, a novel sequential-targeting strategy is developed, in which antifibrotic fraxinellone-loaded CGKRK-modified nanoparticles (Frax-NP-CGKRK) are constructed to regulate TGF-ß signaling and siRNA-loaded lipid-coated calcium phosphate (LCP) biomimetic nanoparticles (siKras-LCP-ApoE3) are applied to interfere with the oncogenic KRAS. Frax-NP-CGKRK successfully targets the tumor sites through the recognition of overexpressed heparan sulfate proteoglycan, reverses the activated cancer-associated fibroblasts (CAFs), attenuates the dense stroma barrier, and enhances tumor blood perfusion. Afterward, siKras-LCP-ApoE3 is efficiently internalized by the tumor cells through macropinocytosis and specifically silencing KRAS mutation. Compared with gemcitabine, this sequential-targeting strategy significantly elongates the lifespans of pancreatic tumor-bearing animals, hence providing a promising approach for pancreatic cancer therapy.

Overexpression of FoxO3a is associated with glioblastoma progression and predicts poor patient prognosis.

Forkhead transcription factor FoxO3a has been reported to have ambiguous functions and distinct mechanisms in various solid tumors, including glioblastoma (GBM). Although a preliminary analysis of a small sample of patients indicated that FoxO3a aberrations in glioma might be related to aggressive clinical behavior, the clinical significance of FoxO3a in glioblastoma remains unclear. We investigated the expression of FoxO3a in a cohort of 91 glioblastoma specimens and analyzed the correlations of protein expression with patient prognosis. Furthermore, the functional impact of FoxO3a on GBM progression and the underlying mechanisms of FoxO3a regulation were explored in a series of in vitro and in vivo assays. FoxO3a expression was elevated in glioblastoma tissues, and high nuclear FoxO3a expression in human GBM tissues was associated with poor prognosis. Moreover, knockdown of FoxO3a significantly reduced the colony formation and invasion ability of GBM cells, whereas overexpression of FoxO3a promoted the colony formation and invasion ability. The results of in vivo GBM models further confirmed that FoxO3a knockdown inhibited GBM progression. More, the pro-oncogenic effects of FoxO3a in GBM were mediated by the activation of c-Myc, microtubule-associated protein 1 light chain 3 beta (LC3B) and Beclin1 in a mixed-lineage leukemia 2 (MLL2)-dependent manner. These findings suggest that high FoxO3a expression is associated with glioblastoma progression and that FoxO3a independently indicates poor prognosis in patients. FoxO3a might be a novel prognostic biomarker or a potential therapeutic target in glioblastoma.

High-density lipoprotein-biomimetic nanocarriers for glioblastoma-targeting delivery: the effect of shape.

Rational design of the physicochemical properties of nanocarriers can optimize their pharmacokinetics, biodistribution, intratumoral penetration and tumor bioavailability. In particular, particle shape is one of the crucial parameters that can impact the circulation time, tumor accumulation and tumor cell internalization of nanocarrier. Biomimetic reconstituted high-density lipoprotein (rHDL), by mimicking the endogenous shape and structure of high-density lipoprotein, has been indicated as a promising tumor-targeting nanoparticulate drug delivery system whereas the effect of shape on tumor-targeting efficiency has not been fully evaluated. Herein, we constructed apolipoprotein E-based biomimetic rHDL in both discoidal form (d-rHDL) and spherical form (s-rHDL), and compared their efficiency in glioblastoma multiforme (GBM)-targeting delivery. s-rHDL showed higher cellular association in GBM cells especially at a high exposure dosage or after a long incubation time. Moreover, it exhibited deeper penetration in 3D GBM spheroids in vitro and higher accumulation at the GBM site in vivo with the GBM-targeting accumulation of s-rHDL increased by 73% when compared with that of d-rHDL at 24 h post-injection. The findings collectively indicated that s-rHDL might serve as a more efficient nanocarrier for glioblastoma-targeting drug delivery.

Intranasal drug delivery: The interaction between nanoparticles and the nose-to-brain pathway.

Intranasal delivery provides a direct and non-invasive method for drugs to reach the central nervous system. Nanoparticles play a crucial role as carriers in augmenting the efficacy of brain delivery. However, the interaction between nanoparticles and the nose-to-brain pathway and how the various biopharmaceutical factors affect brain delivery efficacy remains unclear. In this review, we comprehensively summarized the anatomical and physiological characteristics of the nose-to-brain pathway and the obstacles that hinder brain delivery. We then outlined the interaction between nanoparticles and this pathway and reviewed the biomedical applications of various nanoparticulate drug delivery systems for nose-to-brain drug delivery. This review aims at inspiring innovative approaches for enhancing the effectiveness of nose-to-brain drug delivery in the treatment of different brain disorders.

Intracerebral fate of organic and inorganic nanoparticles is dependent on microglial extracellular vesicle function.

Nanoparticles (NPs) represent an important advance for delivering diagnostic and therapeutic agents across the blood-brain barrier. However, NP clearance is critical for safety and therapeutic applicability. Here we report on a study of the clearance of model organic and inorganic NPs from the brain. We find that microglial extracellular vesicles (EVs) play a crucial role in the clearance of inorganic and organic NPs from the brain. Inorganic NPs, unlike organic NPs, perturb the biogenesis of microglial EVs through the inhibition of ERK1/2 signalling. This increases the accumulation of inorganic NPs in microglia, hindering their elimination via the paravascular route. We also demonstrate that stimulating the release of microglial EVs by an ERK1/2 activator increased the paravascular glymphatic pathway-mediated brain clearance of inorganic NPs. These findings highlight the modulatory role of microglial EVs on the distinct patterns of the clearance of organic and inorganic NPs from the brain and provide a strategy for modulating the intracerebral fate of NPs.

Comparative Proteomics Inspired Self-Stimulated Release Hydrogel Reinforces the Therapeutic Effects of MSC-EVs on Alzheimer's Disease.

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.

Self-Disassembling and Oxygen-Generating Porphyrin-Lipoprotein Nanoparticle for Targeted Glioblastoma Resection and Enhanced Photodynamic Therapy.

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.

Brain Delivery of Protein Therapeutics by Cell Matrix-Inspired Biomimetic Nanocarrier.

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.

Targeted drug delivery system inspired by macropinocytosis.

Macropinocytosis is a widely-observed and evolutionarily-conserved endocytic process found in the eukaryotic cells. In comparison to other endocytic routes, macropinocytosis allows for the internalization of greater quantities of fluid-phase drugs, making it an attractive avenue for drug delivery. Recent evidence showed that various drug delivery systems can be internalized through macropinocytosis. Utilizing macropinocytosis may therefore provide a new avenue for targeted intracellular delivery. In this review, we provide an overview into the origins and distinctive properties of macropinocytosis, summarize the roles of macropinocytosis under healthy and pathological settings. Furthermore, we highlight the biomimetic and synthetic drug delivery systems that employ macropinocytosis as the primary internalization mechanism. To facilitate the clinical applications of these drug delivery systems, additional research can be conducted to enhance the cell-type selectivity of macropinocytosis, the control of drug release at the target, and the prevention of potential toxicity. The rapidly emerging field of macropinocytosis-based targeted drug delivery and therapies holds great potential to drastically increase the efficiency and specificity of drug delivery.

Steroid-loaded reconstituted high-density lipoprotein nanocarrier: A new treatment for systemic lupus erythematosus.

Glucocorticoids (GCs) are the most effective and commonly used drugs for the treatment of systemic lupus erythematosus (SLE). However, a large number of side effects occur after long-term or high-dose glucocorticoid treatment, which severely restricts the use of glucocorticoids. Reconstituted high-density lipoprotein (rHDL), an emerging nanocarrier, is promising for targeted delivery to sites of inflammation and macrophages. Here, we prepared a steroid-loaded recombinant high-density lipoprotein and evaluated its therapeutic efficacy in a murine macrophage cell line (RAW264.7) and a lupus (MRL/lpr mice) mouse model. The obtained corticosteroid-loaded nanomedicine, named PLP-CaP-rHDL, exhibited desirable characteristics. Pharmacodynamics studies revealed that the nanoparticles could significantly reduce the levels of inflammatory cytokines in the macrophages in vitro and also effectively alleviate lupus nephritis in MRL/lpr mice without causing obvious side effects at a dose of 0.25 mg/kg. Thus, our newly developed steroid-loaded rHDL nanocarriers hold a great potential for anti-inflammatory therapy with reduced side effects and may provide a precise targeted therapy for SLE.

Nano-Brake Halts Mitochondrial Dysfunction Cascade to Alleviate Neuropathology and Rescue Alzheimer's Cognitive Deficits.

Mitochondrial dysfunction has been recognized as the key pathogenesis of most neurodegenerative diseases including Alzheimer's disease (AD). The dysregulation of mitochondrial calcium ion (Ca2+ ) homeostasis and the mitochondrial permeability transition pore (mPTP), is a critical upstream signaling pathway that contributes to the mitochondrial dysfunction cascade in AD pathogenesis. Herein, a "two-hit braking" therapeutic strategy to synergistically halt mitochondrial Ca2+ overload and mPTP opening to put the mitochondrial dysfunction cascade on a brake is proposed. To achieve this goal, magnesium ion (Mg2+ ), a natural Ca2+ antagonist, and siRNA to the central mPTP regulator cyclophilin D (CypD), are co-encapsulated into the designed nano-brake; A matrix metalloproteinase 9 (MMP9) activatable cell-penetrating peptide (MAP) is anchored on the surface of nano-brake to overcome the blood-brain barrier (BBB) and realize targeted delivery to the mitochondrial dysfunction cells of the brain. Nano-brake treatment efficiently halts the mitochondrial dysfunction cascade in the cerebrovascular endothelial cells, neurons, and microglia and powerfully alleviates AD neuropathology and rescues cognitive deficits. These findings collectively demonstrate the potential of advanced design of nanotherapeutics to halt the key upstream signaling pathways of mitochondrial dysfunction to provide a powerful strategy for AD modifying therapy.

Recombinant High-Density Lipoprotein Boosts the Therapeutic Efficacy of Mild Hypothermia in Traumatic Brain Injury.

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.

Nanopolyphenol rejuvenates microglial surveillance of multiple misfolded proteins through metabolic reprogramming.

Microglial surveillance plays an essential role in clearing misfolded proteins such as amyloid-beta, tau, and α-synuclein aggregates in neurodegenerative diseases. However, due to the complex structure and ambiguous pathogenic species of the misfolded proteins, a universal approach to remove the misfolded proteins remains unavailable. Here, we found that a polyphenol, α-mangostin, reprogrammed metabolism in the disease-associated microglia through shifting glycolysis to oxidative phosphorylation, which holistically rejuvenated microglial surveillance capacity to enhance microglial phagocytosis and autophagy-mediated degradation of multiple misfolded proteins. Nanoformulation of α-mangostin efficiently delivered α-mangostin to microglia, relieved the reactive status and rejuvenated the misfolded-proteins clearance capacity of microglia, which thus impressively relieved the neuropathological changes in both Alzheimer's disease and Parkinson's disease model mice. These findings provide direct evidences for the concept of rejuvenating microglial surveillance of multiple misfolded proteins through metabolic reprogramming, and demonstrate nanoformulated α-mangostin as a potential and universal therapy against neurodegenerative diseases.

Reprogramming systemic and local immune function to empower immunotherapy against glioblastoma.

The limited benefits of immunotherapy against glioblastoma (GBM) is closely related to the paucity of T cells in brain tumor bed. Both systemic and local immunosuppression contribute to the deficiency of tumor-infiltrating T cells. However, the current studies focus heavily on the local immunosuppressive tumor microenvironment but not on the co-existence of systemic immunosuppression. Here, we develop a nanostructure named Nano-reshaper to co-encapsulate lymphopenia alleviating agent cannabidiol and lymphocyte recruiting cytokine LIGHT. The results show that Nano-reshaper increases the number of systemic T cells and improves local T-cell recruitment condition, thus greatly increasing T-cell infiltration. When combined with immune checkpoint inhibitor, this therapeutic modality achieves 83.3% long-term survivors without recurrence in GBM models in male mice. Collectively, this work unveils that simultaneous reprogramming of systemic and local immune function is critical for T-cell based immunotherapy and provides a clinically translatable option for combating brain tumors.

Synthetically Lethal Biomimetic Nutri-hijacker Hitchhikes and Reprograms KRAS Mutation-Driven Metabolic Addictions for Pancreatic Ductal Adenocarcinoma Treatment.

Metabolic therapy targeting the metabolic addictions driven by gain-of-function mutations in KRAS is promising in fighting cancer through selective killing of malignant cells without hurting healthy cells. However, metabolic compensation and heterogeneity make current metabolic therapies ineffective. Here, we proposed a biomimetic "Nutri-hijacker" with "Trojan horse" design to induce synthetic lethality in KRAS-mutated (mtKRAS) malignant cells by hitchhiking and reprogramming the metabolic addictions. Nutri-hijacker consisted of the biguanide-modified nanoparticulate albumin that impaired glycolysis and a flavonoid that restrained glutaminolysis after the macropinocytosis of Nutri-hijacker by mtKRAS malignant cells. Nutri-hijacker suppressed the proliferation and spread of mtKRAS malignant cells while lowering tumor fibrosis and immunosuppression. Nutri-hijacker significantly extended the lifespan of pancreatic ductal adenocarcinoma (PDAC)-bearing mice when combined with the hydroxychloroquine-based therapies that failed in clinical trials. Collectively, our findings demonstrated that Nutri-hijacker is a strong KRAS mutation-customized inhibitor and the synthetic lethality based on mtKRAS-driven metabolic addictions might be a promising strategy against PDAC.

Nano-Plumber Reshapes Glymphatic-Lymphatic System to Sustain Microenvironment Homeostasis and Improve Long-Term Prognosis after Traumatic Brain Injury.

Traumatic brain injury (TBI) is a leading cause of death and disability worldwide. Long-term changes in the microenvironment of the brain contribute to the degeneration of neurological function following TBI. However, current research focuses primarily on short-term modulation during the early phases of TBI, not on the critical significance of long-term homeostasis in the brain microenvironment. Notably, dysfunction of the glymphatic-lymphatic system results in the accumulation of danger/damage-associated molecular patterns (DAMPs) in the brain, which is regarded as the leading cause of long-term microenvironmental disturbances following TBI. Here, a nanostructure, Nano-plumber, that co-encapsulates the microenvironment regulator pro-DHA and the lymphatic-specific growth factor VEGF-C is developed, allowing for a sustainable and orderly regulation of the microenvironment to promote long-term neurological recovery. Nano-plumber reverses the injury microenvironment by suppressing microglia and astrocytes activation and maintaining reduced activation via enhanced glymphatic-lymphatic drainage, and significantly improves the neurological function of rodents with TBI. This study demonstrates that glymphatic-lymphatic system reconstruction is essential for enhancing long-term prognosis following TBI, and that the Nano-plumber developed here may serve as a clinically translatable treatment option for TBI.