(A) Schematic of two-step structure activity screening using yREX3 as a template. Locked nucleic acids are shown in red. (B) Pick1 downregulation screening of synthetic candidates. (C) Stability of yREX3 and TY2 exposed to increasing concentrations of RNAse R. (D) Efferocytosis assay showing uptake of DiD-labeled dead rat cardiomyocytes by rat macrophages at 48 hours. (E–G) TTC staining showing infarct size (E and F) and ELISA of circulating cardiac troponin I (cTnI) (G) in rats with MI receiving yREX3 or TY2 i.v. or orally by gavage after reperfusion. (H) Cecal ligation and puncture–induced (CLP-induced) polymicrobial sepsis model was induced at day 0. Numbers represent days. (I) Kaplan-Meier curve showing survival of treatment groups (sham, n = 5; vehicle, n = 8; TY2, n = 9). (J) Echocardiographic measurement of cardiac function (fractional shortening [FS] %) at day 1 and day 7. (K) Left ventricular internal diameter (LVID; mm). (L) Bacterial burden in tissue measured in hearts (L) and lungs (M) using qPCR of bacterial 16S. (N and O) Assessment of bacterial (E. coli) clearance by bone marrow–derived macrophages exposed to vehicle or TY2. Scale bar: 200 μm. (P and Q) PSMAD3 and CD68 expression in heart sections of mice receiving vehicle or TY2 at 72 hours. Scale bar: 100 μm. Data are presented as mean ± SEM. Dots represent single animals. Statistical analysis of two groups was by Student’s unpaired 2-tailed t test, with 95% CI (C, N, and Q) and that of 3 or more groups was by 1-way ANOVA with Tukey’s (D, J, and K) or Dunnett’s (B, F, G, L, and M, vs. Veh) post test. *P < 0.05, **P < 0.01, ***P < 0.001, and ****P < 0.0001.