Biomimetic Nanoparticle-Mediated Target Delivery of Hypoxia-Responsive Plasmid of Angiotensin-Converting Enzyme 2 to Reverse Hypoxic Pulmonary Hypertension

Abstract

Hypoxic pulmonary hypertension (HPH) is characterized by pulmonary vascular sustained constriction and progressive remodeling, which are initiated by hypoxia then with hypoxia-induced additive factors including pulmonary vascular endothelium injury, intrapulmonary angiotension system imbalance, and inflammation. Now HPH is still an intractable disease lacking effective treatments. Gene therapy has a massive potential for HPH but is hindered by a lack of efficient targeted delivery and hypoxia-responsive regulation systems for transgenes. Herein, we constructed the hypoxia-responsive plasmid of angiotensin-converting enzyme 2 (ACE2) with endothelial-specific promoter Tie2 and a hypoxia response element and next prepared its biomimetic nanoparticle delivery system, named ACE2-CS-PRT@PM, by encapsulating the plasmid of ACE2 with protamine and chondroitin sulfate as the core then coated it with a platelet membrane as a shell for targeting the injured pulmonary vascular endothelium. ACE2-CS-PRT@PM has a 194.3 nm diameter with a platelet membrane-coating core–shell structure and a negatively charged surface, and it exhibits higher delivery efficiency targeting to pulmonary vascular endothelium and hypoxia-responsive overexpression of ACE2 in endothelial cells in a hypoxia environment. In vitro, ACE2-CS-PRT@PM significantly inhibited the hypoxia-induced proliferation of pulmonary smooth muscle cells. In vivo, ACE2-CS-PRT@PM potently ameliorated the hemodynamic dysfunction and morphological abnormality and largely reversed HPH via inhibiting the hypoxic proliferation of pulmonary artery smooth muscle cells, reducing pulmonary vascular remodeling, restoring balance to the intrapulmonary angiotension system, and improving the inflammatory microenvironment without any detectable toxicity. Therefore, ACE2-CS-PRT@PM is promising for the targeted gene therapy of HPH.

Sniping Cancer Stem Cells with Nanomaterials

“…This incites an intracellular signaling cascade, leading to the interruption of TJs and reorganization of the actin cytoskeleton, consequently enabling CM@AIE NPs to traverse the BBB silently (Figure B) . Aside from deploying membranes derived from a singular cell source such as red blood cell, platelet, immune cell, and cancer cell; hybrid cell membranes also offer a promising strategy . Employing a cancer cell-mitochondria hybrid membrane enables the targeted delivery of OXPHOS inhibitors within GBM, which has facilitated the treatment of GBM stem cell xenografts in mice (Table ).…”

Multistage Self-Assembled Nanomaterials for Cancer Immunotherapy

“…Increasing knowledge in tumor biophysics and biochemistry, especially tumor microenvironments, has promoted the development of stimuli-responsive nanocarriers for precise and specific drug release [195][196][197][198][199][200]. Triggered by internal stimuli such as tumoral acid [201][202][203][204][205][206][207][208], redox [209][210][211][212][213][214][215][216][217][218][219][220][221][222][223][224][225], hypoxia [226][227][228][229][230][231], and enzymes [232][233][234][235][236][237][238][239], or external stimuli like near-infrared (NIR) light and ultrasound [240][241][242...…”

Remotely Controlled Surface Charge Modulation of Magnetoelectric Nanogenerators for Swift and Efficient Drug Delivery

“…Additionally, Yang et al recently demonstrated the effectiveness of tumor-specific PEGylated bilirubin nanoparticles loaded with drug dimers, which suppressed robust 4T1 breast cancer cells . Further, these drug nanocarriers can be classified based on the different triggering mechanisms such as magnetic-responsive, − pH-responsive, light-responsive, enzyme-responsive, and hypoxia-responsive . Xu et al, encapsulated DOX in poly­(acrylic acid) stabilized with amorphous calcium carbonate nanoparticles for sustainable release of drug by sensing the acidic pHs environment zebrafish model for eradication of human hepatocarcinoma cell line (SMCC-7721).…”

“… 22 Further, these drug nanocarriers can be classified based on the different triggering mechanisms such as magnetic-responsive, 23 − 25 pH-responsive, 26 light-responsive, 27 enzyme-responsive, 28 and hypoxia-responsive. 29 Xu et al, 30 encapsulated DOX in poly(acrylic acid) stabilized with amorphous calcium carbonate nanoparticles for sustainable release of drug by sensing the acidic pHs environment zebrafish model for eradication of human hepatocarcinoma cell line (SMCC-7721). However, these pH-sensitive drug release systems do not provide precise control over drug release rates and can lead to unpredictable release kinetics.…”