A targeted and safe strategy for post-infarction anti-inflammatory therapy: cardiac-restricted NLRP3 inhibition via a biomimetic nanocarrier

Background Targeting inflammation is a promising strategy to reduce recurrent events after acute myocardial infarction (AMI), yet current guidelines lack strongly recommended anti-inflammatory therapies. While IL-1β blockade (e.g., canakinumab) reduces events, it elevates fatal infection risk, highlighting the need for more precise approaches. Upstream NLRP3 inhibition (e.g., with MCC950) offers specificity, but its clinical translation has been limited by hepatotoxicity, necessitating a targeted delivery system to achieve local efficacy while avoiding systemic exposure. Purpose To engineer a biomimetic nanocarrier (MPDA-MCC950@LPs-MM) enabling cardiac-restricted delivery of the NLRP3 inhibitor MCC950, aiming to maximize local anti-inflammatory efficacy in myocardial ischemia-reperfusion injury while circumventing dose-limiting systemic toxicity. Methods We engineered a biomimetic nanoplatform (MPDA-MCC950@LPs-MM) by cloaking MCC950-loaded mesoporous polydopamine (MPDA) nanoparticles with cationic liposomes (LPs) and macrophage membranes (MM). The system was characterized for physicochemical properties, membrane protein retention, and ROS/pH-responsive release. Therapeutic efficacy was evaluated in LPS+ATP-stimulated macrophages in vitro and in a murine myocardial ischemia/reperfusion(I/R) model in vivo, with once-daily intravenous administration on post-infarction days 1–3. Results The nanoplatform exhibited a uniform size (~140 nm), preserved MM proteins, and ROS/pH-responsive drug release. The macrophage-membrane coating conferred inflammation-directed cardiac targeting, achieving 2.5-fold higher myocardial accumulation than non-coated nanoparticles. Consequently, MPDA-MCC950@LPs-MM exhibited the most potent suppression of the NLRP3-GSDMD axis, significantly reducing pyroptosis markers (GSDMD-NT, cleaved caspase-1, mature IL-1β; p<0.001) versus free MCC950 and uncoated nanoparticles. This targeted efficacy translated into markedly attenuated fibrosis (~5% vs. ~25%) and preserved cardiac function (LVEF 54.33±3.85% vs. 33.25±11.64% in controls) at day 21 post-I/R, all without detectable hepatotoxicity (normal ALT/AST and hepatic histology). Conclusions In preclinical model, macrophage membrane-coated nanoparticles enabled targeted delivery of MCC950 to the infarcted hearts, robustly inhibiting NLRP3/GSDMD-driven pyroptosis and improving cardiac recovery without systemic toxicity. These findings offer a proof-of-concept for a feasible and safe targeted nanotherapy that decouples anti-inflammatory efficacy from off-target risks, offering a targeted approach to mitigate post-infarction inflammatory injury.