MiR-133a encapsulated in hyaluronic acid nanoparticles alleviates sepsis-induced cardiomyopathy by decreasing M1 macrophage polarization via the SOCS3/JAK/STAT3 pathway

BACKGROUND: Sepsis-induced cardiomyopathy (SIC) is a reversible myocardial dysfunction driven by excessive inflammation, with M1 macrophage polarization as a major contributor. This study explored the regulatory role of the miR-133a/SOCS3 axis in macrophage polarization and myocardial injury and assessed a hyaluronic acid (HA)-based nanogel for targeted miR-133a delivery. METHODS: RAW264.7 macrophages were stimulated with LPS and co-cultured with H9C2 cardiomyocytes, followed by transfection with miR-133a mimics/inhibitor or SOCS3 overexpression plasmids. The direct binding between miR-133a and SOCS3 was verified by dual-luciferase reporter assay. A cecal ligation and puncture (CLP) rat model was used to assess in vivo therapeutic effects after intravenous administration of free or HA-encapsulated miR-133a. Macrophage polarization was measured by flow cytometry and qRT-PCR; inflammatory cytokines by ELISA; protein expression (SOCS3, JAK/STAT3 pathway, iNOS, CD206) by Western blot and immunohistochemistry; apoptosis by TUNEL; and myocardial injury by H&E staining. RESULTS: MiR-133a was significantly downregulated in LPS-treated macrophages and in SIC blood samples, with levels inversely correlated to SOCS3. MiR-133a overexpression suppressed M1 polarization, cytokine production, and SOCS3 expression, while enhancing M2 polarization; these effects were reversed by SOCS3 overexpression. In co-culture, miR-133a reduced cardiomyocyte inflammation and apoptosis through SOCS3/JAK/STAT3 inhibition. In CLP rats, HA-miR-133a achieved greater myocardial accumulation than free mimics, attenuated histopathological damage, lowered cytokine levels, iNOS, and phosphorylated JAK3/STAT3, and increased CD206 expression. CONCLUSION: MiR-133a alleviates SIC by inhibiting SOCS3/JAK/STAT3 signaling and promoting M2 polarization. HA-based targeted delivery enhances stability, tissue uptake, and therapeutic efficacy, representing a promising SIC therapy.