T Lymphocyte-Macrophage Hybrid Membrane-Coated Biomimetic Nanoparticles Alleviate Myocarditis via Suppressing Pyroptosis by Targeting Gene Silencing

Abstract Utilizing small interfering RNA (siRNA) for gene silencing presents a viable strategy for treating human diseases, including cardiovascular disorders. However, the strategic targeting and delivery of siRNA therapeutics to desired tissues or cell subtypes, followed by endosomal escape into the cytosol, remain challenging. Based on previous research, we identified interferon regulatory factor 1 (IRF1)-mediated macrophage pyroptosis as a potential therapeutic target for myocarditis. Herein, a T lymphocyte-macrophage hybrid membrane-coated zeolitic imidazolate framework-8 (ZIF-8) nano-delivery platform was fabricated for the precise conveyance of siRNA against IRF1 (siIRF1) to the pro-inflammatory M1 macrophages in myocarditis (siIRF1@ZIF@HM). The siIRF1-loaded ZIF-8 nanoparticle exhibited a high siRNA loading capacity and efficient endo-lysosomal escape ability. The application of hybrid membrane coating significantly improved M1 macrophage targeting both in vivo and in vitro. Delivery of siIRF1 effectively suppressed IRF1 expression and concomitantly inhibited pyroptosis in IFN-γ-stimulated macrophages. Consequently, the siIRF1 nanotherapeutic approach demonstrated the potential to attenuate myocardial inflammation and mitigate the progression of myocarditis. Our study reveals that the customized biomimetic nano-delivery system holds great prospects in the treatment of inflammatory diseases.