Microneedle patch loaded with immune-evading engineered cell membrane vesicles promotes myocardial repair by blocking the cGAS-STING pathway

Hybrid macrophage/cardiomyocyte membrane coating achieves immune evasion and myocardial targeting. • Pomelo peel cellulose-based microneedles enable 14-day sustained release of ginsenoside Rg1. • The system blocks the mtDNA-cGAS-STING inflammatory axis by preserving mitochondrial integrity. • Treatment promotes M2 macrophage polarization and angiogenesis in infarcted myocardium. • CM@PPG-MNs significantly improve survival and cardiac function in rat myocardial infarction. Myocardial infarction (MI) leads to severe inflammatory reaction and mitochondrial damage, which will inevitably lead to heart failure. There are many problems in the application of traditional nano-carriers, especially the facts that they are easily cleared quickly by the immune system, have poor heart targeting and release drugs too fast. In order to overcome the above problems, a hybrid cell membrane targeted delivery system was designed in this study. In this system, macrophage membrane and myocardial cell membrane were fused, and ginsenoside Rg1 was encapsulated, and then the complex was loaded into a natural pomelo peel cellulose hydrogel microneedle patch to form CM@PPG-MNs. The macrophage membrane component in the carrier can help it escape from immune system attack, while the myocardial cell membrane component can accurately target the damaged myocardial tissue. The microneedle patch can penetrate the surface of the heart and realise the controlled release of ginsenoside Rg1 within the critical 14-day treatment cycle. Studies have confirmed that the system can stop the vicious cycle of inflammation and mitochondrial damage by blocking the mtDNA-cGAS-STING pathway, and at the same time promote the polarization of macrophages from pro-inflammatory M1 type to repair-oriented M2 phenotype. In the rat model of myocardial infarction, the treatment of CM@PPG-MNs patch significantly improved the survival rate of the model animals and reduced the mortality rate from 54.17% to 16.67%. The natural microneedle system developed in this study has excellent efficacy and high application potential in the field of myocardial repair. Schematic illustration of the synthesis, in vivo delivery, and intracellular mechanisms of the macrophage membrane-camouflaged biomimetic microneedle patch (CMV-RG1 Bio-MN Patch) for myocardial infarction treatment, detailing the extraction of cellulose nanofibers and RAW 264.7 macrophage membranes to fabricate a microneedle patch loaded with Rg1 encapsulated nanovesicles (Rg1@CM), which, upon implantation onto the infarcted area, utilizes homologous “self” recognition to evade host macrophage attack and specifically target injured cardiomyocytes, where Rg1 exhibits a dual-pathway blockade by inhibiting the mtDNA-triggered cGAS-STING inflammatory pathway (downregulating IL-1β, IL-6, TNF-a and upregulating IL-4, IL-10) and preventing mitochondrial Cytochrome c release to mitigate ATP depletion, synergistically promoting ROS scavenging, angiogenesis, and M2 macrophage polarization. Download: Download high-res image (200KB) Download: Download full-size image