In-situ programming of tolerogenic DCs mediated via efficient delivery of self-antigen for myocardial ischemia-reperfusion injury immunotherapy.

Myocardial ischemia-reperfusion injury (MIRI) triggers innate immunity and excessive inflammation, which could potentially be reversed by shifting the immune system from activation to tolerance. However, conventional immune interventions predominantly aim to suppress local inflammation within the myocardium, and their effectiveness is limited by challenges associated with targeted delivery to and retention within myocardial tissue. To address this, a novel drug delivery system, designated as PBEPR@Man, has been developed to effectively deliver the highly immunogenic myocardial infarction tissue lysates (MITLs) that address the existing challenges related to the low immunogenicity and limited specificity of mono-antigen strategies. This system was specifically engineered to target lymph nodes, with the aim of enhancing lymph nodes dendritic cells (DCs)-driven immune tolerance in situ. PBEPR@Man promoted tolerogenic DCs generation and antigen-specific regulatory T cells (Tregs) proliferation, which synergistically enhanced immunosuppression. Tregs infiltrated into the infarcted area and promoted M2 macrophage polarization, thereby modulating the inflammatory microenvironment. Results demonstrated that PBEPR@Man effectively suppressed excessive inflammatory responses in myocardial tissue and improved cardiac function. This project will provide a theoretical basis for self-antigen-based immunotherapy for the treatment of MIRI.