Combined intramyocardial injectable hydrogel and pericardial adhesive hydrogel patch therapy strategy to achieve gene/ion/gas delivery for improving cardiac function

Circular RNA (circRNA), bioactive ion and nitric oxide (NO) are beneficial to myocardial repair after myocardial infarction (MI); however, to achieve efficient intervention of circRNA and delivery of NO and ion throughout myocardium still remains difficult. Injectable hydrogels have been frequently used to release angiogenic factors; however, due to the limited drug diffusion distance, angiogenic factors are difficult to reach the epicardium – a viable target for angiogenesis. Herein, a combined strategy based on coadministration of lipo/pcircRNA and strontium ions-containing nanoparticles-encapsulated injectable hydrogel and NO-bearing liposome-loaded pericardial adhesive hydrogel patch is proposed to realize intramyocardial gene/ion delivery and epicardial NO delivery to inhibit cardiomyocyte apoptosis and inflammatory response, and circumvent insufficient angiogenesis problem. The hydrogel prepared via Schiff-reaction of hydrazide-hyaluronic acid and aldehydated-laminarin with self-immunoregulation function is injected into the myocardium to deliver lipo/pcircRNA nanoparticles and strontium ions to inhibit cardiomyocyte apoptosis and partially promote angiogenesis. To further boost angiogenesis, an adhesive hyaluronic acid-based hydrogel is bonded to the myocardial surface by pre-anchored sponge that can remove hydration layer, to achieve the release of NO nanodrug in epicardium. This combination therapy contributes to a significant inhibition of cardiomyocyte apoptosis and inflammatory response and maximum angiogenesis, thus improving cardiac function.