Engineered ETS1-Nanoconjugate Restores Immune Homeostasis through Dual Immune-Vascular Modulation in Relapsing and...

Area of Science:

• Immunology
• Nanotechnology
• Neuroscience

Background:

• Current multiple sclerosis (MS) treatments targeting T or B cells offer limited efficacy due to MS pathogenesis complexity.
• Endothelial-to-mesenchymal transition (EndMT) and immune infiltration create a cycle that worsens blood-brain barrier (BBB) disruption and neuroinflammation in MS.

Purpose of the Study:

• To develop a multifunctional nanodelivery platform (IMNP) for dual vascular-immune modulation in MS.
• To target shared IL7R on endothelial cells and T cells for synergistic therapeutic effects.

Main Methods:

• scRNA-seq identified IL7R as a common target on endothelial cells and pathogenic T cells.
• A nanodelivery platform (IMNP) was engineered with ETS1 plasmid DNA, poly(β-amino ester) (PBAE), an IL7R-targeting peptide (ITP), and a macrophage membrane (MM) coating.
• IMNP's efficacy was evaluated in relapsing-remitting MS (RRMS) and secondary progressive MS (SPMS) models.

Main Results:

• IMNP preferentially accumulated at the vascular endothelium, inhibiting EndMT and preserving BBB integrity.
• IMNP attenuated CD4+ T cell differentiation into pro-inflammatory Th1/Th17 subsets, reducing CNS infiltration.
• The nanoplatform significantly alleviated neuroinflammation, reduced demyelination, and improved motor function in both RRMS and SPMS models.

Conclusions:

• The developed biomimetic nanoplatform (IMNP) demonstrates proof-of-concept for dual vascular-immune modulation in MS.
• IMNP offers a promising therapeutic strategy for both relapsing and progressive forms of MS by re-establishing immune homeostasis.