Nanoparticles coated with immune cell hybrid membranes for targeted delivery of janus kinase inhibitors and synergistic treatment of autoimmune myocarditis.

Abstract

Autoimmune myocarditis is a complicated, inflammatory heart disease with high morbidity and mortality. Interferon (IFN)-γ-mediated classical activated macrophage (M1 macrophage) polarization and pyroptosis play a vital role in immune injury in myocarditis. Baricitinib, a selective Janus kinase (JAK) 1 and JAK2 inhibitor, has been used in the treatment of some systemic autoimmune diseases to effectively suppress pro-inflammatory macrophages by blocking the JAK2-signal transducer and activator of transcription 1 (STAT1) signaling pathway. Nevertheless, its application to autoimmune myocarditis was hindered due to the difficulty of delivering and accumulating the drug in heart tissue. To overcome these limitations, we synthesized a hybrid membrane containing CC motif chemokine receptor (CCR) 1 and CXC motif chemokine receptor (CXCR) 3 from activated RAW264.7 and EL4 cell lines to target inflammatory lesions. Furthermore, mesoporous polydopamine (MPDA) was employed due to its synergistic effects, including high drug loading efficiency, reactive oxygen species (ROS) adsorption, and dual responsiveness to glutathione (GSH) and pH, to fabricate RAW-EL4 hybrid membrane-coated Baricitinib-MPDA nanoparticles (BM@[RAW-EL4] NPs) for Baricitinib delivery. Subsequent in vitro and in vivo experiments verified that BM@[RAW-EL4] NPs significantly inhibited inflammatory infiltration and heart tissue injury by precisely suppressing macrophage polarization and pyroptosis. Biotoxicity and biosafety tests also revealed the biocompatibility of BM@[RAW-EL4] NPs, which provided the foundation for further clinical translation. Hence, the biomimetic BM@[RAW-EL4] NPs offer new heart-specific delivery opportunities, representing a versatile platform for targeted therapy in autoimmune myocarditis. STATEMENT OF SIGNIFICANCE: Autoimmune myocarditis is defined as an intense immune injury in the heart tissue, with current treatment far from satisfactory. IFN-γ-mediated M1 macrophage polarization and pyroptosis are crucial to disease progression. In this study, we created RAW-EL4 hybrid membrane-coated Baricitinib-MPDA nanoparticles (BM@[RAW-EL4] NPs) to achieve targeted delivery of an IFN-γ inhibitor to the inflammatory site. RAW-EL4 hybrid membranes endowed the nanomedicine with chemotactic property under the mechanism of activated CCR1-CCL7/8 and CXCR3-CXCL9/10 axis. MPDA exhibited a high drug-loading efficiency of 49.0 % and dual responsiveness to GSH and pH. We also observed its ability to clear ROS in the study. These characteristics of MPDA promoted the release of Baricitinib and macrophage suppression. In vivo experiments revealed the therapeutic effect and biosafety of BM@[RAW-EL4] NPs for the potential application to autoimmune myocarditis.