Engineered ETS1‐Nanoconjugate Restores Immune Homeostasis through Dual Immune‐Vascular Modulation in Relapsing and Progressive Multiple Sclerosis

ABSTRACT While current treatments for multiple sclerosis (MS) targeting T or B cells have shown clinical benefit, they remain insufficient due to the multifactorial and dynamic nature of MS pathogenesis. A key obstacle to restoring immune homeostasis lies in the reciprocal reinforcement between endothelial‐to‐mesenchymal transition (EndMT) and sustained immune infiltration, which collectively exacerbate blood–brain barrier (BBB) disruption and neuroinflammation. We identified IL7R as a shared target on endothelial cells and pathogenic T cells via scRNA‐seq and developed a multifunctional nanodelivery platform— ETS1 pDNA/PBAE@ITP‐MM (IMNP)—comprising ETS1 plasmid DNA complexed with poly(β‐amino ester) (PBAE), an interleukin‐7 receptor (IL7R)‐targeting peptide (ITP), and a macrophage membrane (MM) coating. IMNP concurrently modulates endothelial cells and T lymphocytes for synergistic efficacy. Exploiting the intrinsic inflammation‐targeting capacity of activated macrophage membranes and ITP conjugation, IMNPs preferentially accumulate at the vascular endothelium, where they inhibit EndMT and preserve BBB integrity. Subsequently, IMNPs attenuate differentiation of CD4 + T cells into proinflammatory Th1/Th17 subsets, thereby reducing CNS infiltration and re‐establishing immune microenvironmental balance in both relapsing‐remitting MS (RRMS) and secondary progressive MS (SPMS) models. Our findings provide proof‐of‐concept for a biomimetic nanoplatform that achieves dual vascular‐immune modulation, significantly alleviating neuroinflammation, reducing demyelination, and improving motor performance in both RRMS and SPMS models.