Combination of an LDH-based platform with microRNA for the treatment of myocardial Ischemia-Reperfusion injury by pyroptosis inhibition via the CaSR/PLCγ1/IP3R pathway

Myocardial ischemia-reperfusion (MI/R) injury, which exacerbates cardiac damage after myocardial infarction (MI), is primarily characterized by oxidative stress and calcium overload, leading to cardiomyocyte pyroptosis. Pyroptosis, further exacerbates the inflammatory response and loss of cardiac function. Therefore, targeting cardiomyocyte pyroptosis is critical for treating MI/R injury. Building on this concept, we developed an innovative layered double hydroxide (LDH)-based nano-platform (LDH@miR-182) that combines the biological effects of LDHs and the protective properties of miR-182. To improve the in vivo applicability of this nano- platform, we introduced biomimetic modifications and evaluated the nano-platform in animal studies. Our findings showed that in addition to stabilizing miR-182 and enhancing its cellular uptake, LDH also exhibited intrinsic reactive oxygen species (ROS)-scavenging and anti-pyroptosis properties. These effects stem not only from the unique structural properties of the platform but also from its regulation of key pathways, including the inhibition of calcium-sensing receptor (CaSR), suppression of phospholipase C gamma 1 (PLC gamma 1) phosphorylation, and blockade of gasdermin D (GSDMD). To address in vivo challenges such as limited targeting and potential immunogenicity, we engineered a macrophage membrane-coated LDH@miR-182 nano-bioplatform (MMLDH@miR-182). This nano-bioplatform exploits the characteristics of the macrophage membrane, prolongs blood circulation, and facilitates inflammation homing. Mechanistically, MM-LDH@miR-182 regulated the CaSR/PLC gamma 1/inositol trisphosphate receptor (IP3R) pathway, reduced calcium release from the endoplasmic reticulum, protected mitochondrial membrane potential, and suppressed mitochondrial ROS production. These synergistic effects effectively inhibited cardiomyocyte pyroptosis, mitigated myocardial fibrosis, and preserved cardiac function. This study presents a novel strategy for targeted MI/R therapy.