Minimalist Nanocomplex with Dual Regulation of Endothelial Function and Inflammation for Targeted Therapy of Inflammatory Vascular Diseases.
Shuo WangYuequan WangXiaoxue LaiJianwen SunMiao HuMeng ChenCong LiFeng XuChuizhong FanXinrong LiuYanzhi SongGuoliang ChenYihui DengPublished in: ACS nano (2023)
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.
Keyphrases
- nuclear factor
- signaling pathway
- nitric oxide synthase
- endothelial cells
- nitric oxide
- prostate cancer
- oxidative stress
- pi k akt
- mouse model
- toll like receptor
- inflammatory response
- high glucose
- ischemia reperfusion injury
- coronavirus disease
- cancer therapy
- cell proliferation
- induced apoptosis
- radical prostatectomy
- cardiovascular disease
- coronary artery disease
- transcription factor
- sars cov
- photodynamic therapy
- genome wide
- hepatitis b virus
- mass spectrometry
- wastewater treatment
- endoplasmic reticulum stress
- vascular endothelial growth factor
- drug release
- capillary electrophoresis
- amino acid