Abstract
BACKGROUND: Sepsis-induced myopathy (SIM) is a severe complication that contributes to late-stage mortality and functional impairment in sepsis patients. The NLRP3 inflammasome plays a pivotal role in the pathogenesis of SIM, and its selective inhibitor MCC950 has shown promising therapeutic potential. However, systemic administration of MCC950 is limited by hepatotoxicity, necessitating the development of targeted delivery systems to enhance efficacy while minimizing toxicity. METHODS: To improve the therapeutic profile of MCC950, we designed M12-functionalized liposomal nanoparticles (M12-Liposome@MCC950 NPs) as the carrier material, with surface modification by the muscle-homing peptide M12 for targeted delivery to skeletal muscle tissue. Nanoparticle characteristics were assessed using transmission electron microscopy (TEM), dynamic light scattering (DLS) and in vitro drug release assays. The targeting efficiency was evaluated in vivo using fluorescence imaging and in vitro via cellular uptake studies in C2C12 myoblasts. The anti-inflammatory and anti-atrophic effects were investigated in an LPS-induced myotube atrophy model and a cecal ligation and puncture (CLP)-induced sepsis mouse model. Biocompatibility and systemic safety were assessed through histological analysis and serum biochemical assays. RESULTS: M12-Liposome@MCC950 NPs exhibited a uniform spherical morphology, an average diameter of 150 ± 10 nm and a zeta potential of -15.73 ± 6.03 mV, ensuring good colloidal stability. The nanoparticles demonstrated sustained drug release over 14 days. In vivo fluorescence imaging confirmed enhanced skeletal muscle accumulation of M12-conjugated nanoparticles, with a 3.47- to 5.31-fold increase compared to nontargeted controls. Cellular uptake studies revealed a 2.28-fold improvement in intracellular delivery efficiency. In vitro, M12-Liposome@MCC950 NPs significantly inhibited NLRP3 inflammasome activation, reducing caspase-1 cleavage and IL-1β/IL-18 secretion, while also preventing LPS-induced myotube atrophy. In the CLP-induced sepsis model, treatment with M12-Liposome@MCC950 NPs markedly reduced muscle atrophy, improved grip strength and decreased expression of atrophy-related proteins Atrogin-1 and MuRF1. Additionally, histological and biochemical assessments confirmed that the nanoparticles did not induce hepatic or renal toxicity, demonstrating excellent biocompatibility. CONCLUSIONS: M12-Liposome@MCC950 NPs provide a targeted and sustained-release strategy for delivering MCC950 to skeletal muscle, effectively inhibiting NLRP3 inflammasome activation and alleviating SIM. This approach enhances therapeutic efficacy while mitigating systemic toxicity, highlighting the potential of nanomedicine-based interventions for treating inflammation-related myopathies.