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Psoriasis is a chronic, immune-mediated inflammatory skin disorder. The vascular endothelium serves as the final barrier preventing circulating immune cells from entering inflamed skin, yet its role in psoriasis pathogenesis and therapeutic potential has long been overlooked. Here, we identify a pathogenic subpopulation of cyclooxygenase-2 (COX2, encoded by PTGS2) high endothelial cells (COX2⁺ ECs), characterized by elevated P-selectin expression, excessive oxidative stress, and MMP9-mediated glycocalyx degradation. The ROS-COX2-MMP9 axis can be effectively suppressed by mebendazole, an FDA-approved anthelmintic drug. Guided by this insight, we develop a bioinspired platform (P@Meb-MNs). Mebendazole and a P-selectin-targeting ligand (PSGL-1) spontaneously self-assemble into carrier-free nanoparticles, which are then encapsulated within an MMP9-responsive microneedle matrix. Upon transdermal administration, the microneedles penetrate the hyperkeratotic epidermis and degrade in response to elevated MMP9 levels, releasing P@Meb-NPs. Directed by PSGL-1, these nanoparticles selectively recognize and accumulate in COX2⁺ ECs, where mebendazole disrupts the ROS-COX2-MMP9 feedback loop, preserves glycocalyx integrity, and suppresses immune cell extravasation. This approach markedly enhances glycocalyx coverage from 11.91 ± 4.09% to 87.5 ± 8.7% and significantly reduces immune cell infiltration. Collectively, this work establishes a vascular-targeted therapeutic paradigm centered on endothelial glycocalyx repair and achieves precise and effective intervention in inflammatory diseases.