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

Abstract

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.

Impaired Meningeal Lymphatics and Glymphatic Pathway in Patients with White Matter Hyperintensity

“…Developing a nano‐plumber that coencapsulates the microenvironment regulator pro‐DHA and the lymphatic‐specific growth factor VEGF‐C, Chen et al significantly improves the neurological function of rodents with traumatic brain injury through enhanced glymphatic‐lymphatic drainage, suppressed microglia and astrocytes activation. [ 31 ] Overexpression of VEGF‐C improves clearance of senescent astrocytes and mitigates neuroinflammation. [ 32 ] Notably, VEGF‐C also shines a light on brain tumors.…”

The contribution of the meningeal immune interface to neuroinflammation in traumatic brain injury

“…MRI of a closed-head impact model of engineered rotational acceleration (CHIMERA) shows meningeal enhancement 7d after single and repeat injury, reflecting clinical observations [ 305 ]. Controlled cortical impact (CCI) in mice presents mixed findings: Lyve-1 + morphology is increased at 7 d (impact 1.5 mm) [ 306 ], with contrasting studies showing decreases at 3 d (impact 2 mm) [ 307 ], and 1 month (impact undisclosed) [ 308 ], highlighting the nuanced and variable nature of spontaneous lymphangiogenic responses across varied mechanisms of impact and injury parameters. Regardless, if plasticity of the lymphatic network can be induced, it may be beneficial to improve outcomes (Fig.…”

“…2 ). Indeed, across models of TBI, overexpression of VEGF-C drives lymphangiogenesis, enhances functional drainage and improves injury induced neurological deficits, including those seen in aged animals [ 303 , 304 , 306 , 308 – 310 ].…”

“…↑IFNβ, IRF5, IFNAR1 At 1.5m ↑ collagen, fibroblasts ↑T/B cell DEG. Aging amplified [ 302 ] 2023 FPI (11°, 2.6 ± 0.16 atm) Male, Sprague–Dawley rats 7 d Whole mount meninges & dCLN *FPI ↓MLVs drainage to dCLN ↓Lyve1, Prox1, Foxc2, VEGFR3 *FPI + VEGF-C/Ketoprofen/RA improves Lyve1 + dCLN drainage [ 304 ] 2023 CCI (1.5 mm, 3m/s, d well time 120 ms) (8–10 wks) 4 d, 7 d, 14 d Whole mount meninges & dCLN *CCI ↓MLVs drainage to dCLN 4 d, 7 d,14 d. ↑Lyve1 7 d *CCI + VEGF-C 156S&EVs@Gel restores dCLN drainage [ 306 ] 2023 FPI (1.9 ± 0.2 atm) Male, Female C57Bl/6 mice (8–10 wks) 3 d Whole mount meninges & dCLN *FPI ↓MLVs drainage to dCLN ↓Lyve1, ↓VEGFC/VEGFR3 *FPI + IL-33 (i.c.m, 20ng/μl, 5 μl), restores dCLN drainage, Lyve1, VEGFC/VEGFR3 [ 303 ] 2023 CCI (2 mm, 3.5 m/s, dwell time 500 ms) Male C57Bl/6 mice (3 months) 28 d Regrown cavity leptomeninges (pia, arachnoid) Brain Fibroblasts (BFB 2–5) ↑Fmod (BFB2/3), ↑Dpp4 (BFB4), ↑Slc47a1 (BFB5) (drug transporter) [ 184 ] 2023 CCI (depth, velocity, undisclosed) Male C57Bl/6 mice (6–10 wks) 28 d Whole mount meninges *CCI ↓Lyve-1 area at 28d *CCI+ pVEGFC (i.v 50µg @1 d, 3 d, 5 d) restores Lyve1 (lymphangiogenesis) [ 308 ] 2023 CCI (1.5 mm, 5.25 m/s, dwell time 100 ms) Male C57Bl/6J mice (8–12 wks & 18–19 m) 7 d, 1 m Meningeal bulk RNA-seq At 7d ↑laminin, collagen and T-cell DEGs. ↑ TGFβ, IFNα.…”

The emerging importance of skull-brain interactions in traumatic brain injury

“…Following injury, the rate of paravascular drainage is slowed by as much as 60%, causing a subsequent reduction in the movement of interstitial fluid through the brain and an increase in protein accumulation in the parenchyma (67). Furthermore, it has recently been shown that enhancement of glymphatic-lymphatic drainage via a "nano-plumber" technology results in a significant improvement in neurological function in rodents following TBI (68). This treatment works by returning injured tissue to a homeostatic microenvironment via dampening the local microglial response and recovering healthy vascular and glymphatic-meningeal lymphatic circulation to support the clearance of noxious material and pro-inflammatory immune cells.…”