Unlockable Nanocomplexes with Self‐Accelerating Nucleic Acid Release for Effective Staged Gene Therapy of Cardiovascular Diseases

Abstract

Nucleic acid (NA)-based therapy is proposed to address serious diseases such as cardiovascular diseases (CVDs). Powerful NA delivery vehicles are essential for effective gene therapy. Herein, a novel type of delivery vehicle, an unlockable core-shell nanocomplex (Hep@PGEA) with self-accelerating NA release, is structurally designed. Hep@PGEA is composed of disulfide-bridged heparin nanoparticle (HepNP) core and low-toxicity PGEA cationic shell. In comparison with NA, heparin, a negatively charged polysaccharide macromolecule, exhibits stronger interactions with cationic species. Upon the breakdown of redox-responsive HepNP cores, unlocked heparin would interact with the outer cationic shells and replace the condensed NA to facilitate NA release. Such unique Hep@PGEA is successfully explored for effective miRNA-pDNA staged gene therapy of myocardial infarction (MI), one of the most serious CVDs. With the progression of MI, glutathione amounts in heart tissues increase. MiR-499 (for the inhibition of cardiomyocyte apoptosis) and plasmid encoding vascular endothelial growth factor (for the promotion of angiogenesis) are sequentially delivered for systemic treatment of MI. Such treatment produces impressive results in restoring heart function and suppressing cardiac hypertrophy. Due to the wide existence of redox agents in cells, the proposed unlockable delivery nanovehicle and staged therapy strategy can provide new methods to effectively treat different serious diseases.

A Hybrid Nanovector of Suicide Gene Engineered Lentivirus Coated with Bioreducible Polyaminoglycosides for Enhancing Therapeutic Efficacy against Glioma

“…Particularly, the SS‐HPT/Lv‐CD group produced the best antitumor performance (Figure c), which was in agreement with the enhanced glioma killing effect in vitro (Figure a). The animal body weight loss represents a toxic indicator of gene vectors . As shown in Figure d, all four groups had no obvious negative impact throughout the experiment period, indicating the good in vivo biocompatibility of SS‐HPT/Lv‐CD.…”

“…Biodegradability represents another crucial parameter of gene vectors. SS‐HPT with disulfide bonds in its backbone could be degraded by reducible molecules such as glutathione (GSH) . Polymers with disulfide bonds were designed as gene vectors, aiming at facilitating the release of target gene from polyplexes and reducing the cytotoxicity of vectors.…”

“…Polymers with disulfide bonds were designed as gene vectors, aiming at facilitating the release of target gene from polyplexes and reducing the cytotoxicity of vectors. [9d,17,18] The content of GSH in tumor cells is several times higher than that in normal cells, which is one of many characteristic aspects in tumor cells . As shown in Figure e, the contents of GSH in the corresponding C6 and U251MG glioma cells were approximately 4.2‐ and 2.3‐folds compared to normal brain cells, which would endow SS‐HPT/Lv with better performance in glioma cells.…”

A novel GSH responsive poly(alpha-lipoic acid) nanocarrier bonding with the honokiol-DMXAA conjugate for combination therapy

“…Of these aspects, as the GSH concentration of the malignant tissues is at least four-fold higher than that of the normal tissues [20][21][22], and the intracellular concentration of GSH is much higher than that in most extracellular fluids [23,24], many new GSH responsive nanoparticles achieved selective release of drugs at tumors [25]. However, most of them were prepared by complex process, such as modifying side groups [26]. In our recent study, GSH responsive nanocarriers were simply prepared by the ringopening polymerization (ROP) of alpha-lipoic acid [27].…”

Wearable and Implantable Devices for Cardiovascular Healthcare: from Monitoring to Therapy Based on Flexible and Stretchable Electronics

“…The heart is a vital organ that pumps blood through blood vessels to provide oxygen (O 2 ) and nutrients throughout the entire body and to remove carbon dioxide (CO 2 ) and metabolic waste from the body. The World Health Organization estimated that cardiovascular diseases (CVDs), i.e., heart and blood vessel diseases, are responsible for up to ≈30% of the total number of deaths worldwide . Since CVDs become much easier to manage when detected early, there is an increasing need for continuous cardiovascular monitoring .…”