No abstract

Vascular disorders, characterized by vascular endothelial dysfunction combined with inflammation, are correlated with numerous fatal diseases, such as coronavirus disease-19 and atherosclerosis. Achieving vascular normalization is an urgent problem that must be solved when treating inflammatory vascular diseases. Inspired by the vascular regulatory versatility of nitric oxide (NO) produced by endothelial nitric oxide synthase (eNOS) catalyzing l-arginine (l-Arg), the eNOS-activating effects of l-Arg, and the powerful anti-inflammatory and eNOS-replenishing effects of budesonide (BUD), we constructed a bi-prodrug minimalist nanoplatform co-loaded with BUD and l-Arg via polysialic acid (PSA) to form BUD-l-Arg@PSA. This promoted vascular normalization by simultaneously regulating vascular endothelial dysfunction and inflammation. Mediated by the special affinity between PSA and E-selectin, which is highly expressed on the surface of activated endothelial cells (ECs), BUD-l-Arg@PSA selectively accumulated in activated ECs, targeted eNOS expression and activation, and promoted NO production. Consequently, the binary synergistic regulation of the NO/eNOS signaling pathway occurred and improved vascular endothelial function. NO-induced nuclear factor-kappa B alpha inhibitor (IκBα) stabilization and BUD-induced nuclear factor-kappa B (NF-κB) response gene site occupancy achieved dual-site blockade of the NF-κB signaling pathway, thereby reducing the inflammatory response and inhibiting the infiltration of inflammation-related immune cells. In a renal ischemia-reperfusion injury mouse model, BUD-l-Arg@PSA reduced acute injury. In an atherosclerosis mouse model, BUD-l-Arg@PSA decreased atherosclerotic plaque burden and improved vasodilation. This represents a revolutionary therapeutic strategy for inflammatory vascular diseases.

No abstract

Immune checkpoint blockade (ICB) treatment for the clinical therapy of numerous malignancies has attracted widespread attention in recent years. Despite being a promising treatment option, developing complementary strategies to enhance the proportion of patients benefiting from ICB therapy remains a formidable challenge because of the complexity of the tumor microenvironment. Ibrutinib (IBR), a covalent inhibitor of Bruton's tyrosine kinase (BTK), has been approved as a clinical therapy for numerous B-cell malignancies. IBR also irreversibly inhibits interleukin-2 inducible T cell kinase (ITK), an essential enzyme in Th2-polarized T cells that participates in tumor immunosuppression. Ablation of ITK by IBR can elicit Th1-dominant antitumor immune responses and potentially enhance the efficacy of ICB therapy in solid tumors. However, its poor solubility and rapid clearance in vivo restrict T cell targetability and tumor accumulation by IBR. A sialic acid derivative-modified nanocomplex (SA-GA-OCT@PC) has been reported to improve the efficacy of IBR-mediated combination immunotherapy in solid tumors. In vitro and in vivo experiments showed that SA-GA-OCT@PC effectively accumulated in tumor-infiltrating T cells mediated by Siglec-E and induced Th1-dominant antitumor immune responses.