Inverse Vaccine Nanomimics: In situ Antigen-Specific Immune Tolerance Induction for Durable Cardiac Repair Post-Myocardial Infarction.

Alleviating the inflammatory response by inducing immune tolerance to cardiomyocyte lysate antigens has been shown to be a promising therapeutic approach for treating myocardial infarction (MI). However, immune tolerance induced by allogeneic antigens is constrained by insufficient antigen specificity, safety risks, and transient therapeutic efficacy. Herein, we present an injectable hydrogel capable of environment-responsive, long-acting delivery of inverse vaccine nanomimics (IVNMs) to overcome these challenges. These IVNMs efficiently capture antigens released by dying cardiomyocytes through the orthogonal reaction between surface maleimide groups and antigen thiols and promote mannose-facilitated uptake by CD206-expressing immune cells, including dendritic cells (DCs). The antigens captured by IVNMs, together with the sustained release of rapamycin from IVNMs, promote the differentiation of DCs into tolerogenic DCs, leading to a persistent increase in regulatory T cells and the establishment of immune tolerance memory. In post-MI rat models, myocardial inflammation was markedly and persistently alleviated, accompanied by enhanced neovascularization and reduced fibrosis, contributing to a sustained cardioprotective effect.