The main culprit in the pathogenesis of ischemia/reperfusion (I/R) injury is the overproduction of reactive oxygen species (ROS). Hydrogen peroxide (H2O2), the most abundant form of ROS produced during I/R, causes inflammation, apoptosis and subsequent tissue damages. Here, we report H2O2-responsive antioxidant nanoparticles formulated from copolyoxalate containing vanillyl alcohol (VA) (PVAX) as a novel I/R-targeted nanotherapeutic agent. PVAX was designed to incorporate VA and H2O2-responsive peroxalate ester linkages covalently in its backbone. PVAX nanoparticles therefore degrade and release VA, which is able to reduce the generation of ROS, and exert anti-inflammatory and anti-apoptotic activity. In hind-limb I/R and liver I/R models in mice, PVAX nanoparticles specifically reacted with overproduced H2O2 and exerted highly potent anti-inflammatory and anti-apoptotic activities that reduced cellular damages. Therefore, PVAX nanoparticles have tremendous potential as nanotherapeutic agents for I/R injury and H2O2-associated diseases.

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Efficient delivery of small interfering RNA (siRNA) is one of major challenges in the successful applications of siRNA in clinic. In the present study, we report a new acid-degradable poly(ketal amidoamine) (PKAA) as a siRNA carrier, which has high delivery efficiency and low cytotoxicity. PKAA was designed to have acid-cleavable ketal linkages in the backbone of cationic biodegradable poly(amidoamine). PKAA efficiently self-assembled with siRNA to form nanocomplexes with a diameter of ~200 nm and slightly positive charges, which are stable under physiological conditions, but rapidly release siRNA at acidic pH. PKAA exhibited sufficient buffering capability and endosomolytic activity due mainly to the presence of secondary amine groups in its backbone and rapid degradation in acidic endosomes, leading to the enhanced release of siRNA to cytoplasm. Cell culture studies demonstrated that PKAA is capable of delivering anti-TNF (tumor necrosis factor)-α siRNA to lipopolysaccharide (LPS)-stimulated macrophages and significantly inhibits the expression of TNF-α. A mouse model of acetaminophen (APAP)-induced acute liver failure was used to evaluate in vivo siRNA delivery efficacy of PKAA. PKAA/anti-TNF-α siRNA nanocomplexes significantly reduced the ALT (alanine transaminase) and the hepatic cellular damages in APAP-intoxicated mice. We anticipate that acid-degradable PKAA has great potential as siRNA carriers based on its excellent biocompatibility, pH sensitivity, potential endosomolytic activity, and high delivery efficiency.

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The structural performance of nailed hold-down connection systems used for cross-laminated timber (CLT) shear walls under monotonic and cyclic loading was experimentally evaluated. Critical connection performance parameters, including strength, stiffness, ductility, and overstrength, were derived from the testing of 68 hold-down connection specimens. The nailed CLT hold-down connections achieved moderate to high ductility when fracture failures of their metal brackets were avoided. The hold-down connection systems with 3 mm thick commercial brackets achieved ductility factors ranged from 2.7 to 4.3, while the hold-down connection systems composed of 10 mm thick steel plates and longer nails achieved larger ductility factors which ranged from 4.7 to 6.3. The overstrength factors of the holddown systems ranged from 1.45 to 1.62 except the one composed of the 10 mm thick brackets and 100 mm long nails installed at wide spacing. It was also found that the yield strength of the nailed hold-down connections under monotonic loading was similar to that obtained by cyclic loading.