Nanoparticle-enabled CD40 silencing programs immune tolerance via a DC-Treg-Breg axis in autoimmune myocarditis

Autoimmune myocarditis is a severe inflammatory heart disease that can progress to dilated cardiomyopathy and heart failure, while disease-modifying therapies remain limited. Dysregulated activation of antigen-presenting cells, particularly dendritic cells (DCs), disrupts immune tolerance and drives pathogenic cardiac inflammation. Here, we report a nanoparticle-enabled CD40 silencing strategy for immune tolerance programming in experimental autoimmune myocarditis. Using a polymer-lipid hybrid siRNA formulation, we achieved sustained CD40 silencing in myeloid antigen-presenting cells and induced functional reprogramming of DCs toward a tolerogenic state. This intervention established a coordinated DC-centered regulatory circuit, characterized by expansion of Foxp3⁺ regulatory T cells and IL-10-producing regulatory B cells, together with suppression of pathogenic Th17 responses. Functionally, siCD40/NP treatment attenuated myocardial inflammation, limited chronic fibrotic remodeling, and preserved ventricular function without evidence of overt systemic toxicity. Notably, regulatory B cells were enriched in cardiac-draining lymphoid tissues during the chronic phase, suggesting a spatially organized tolerance mechanism that contributes to durable disease control. Collectively, these findings identify nanoparticle-enabled CD40 silencing as a materials-based strategy for immune tolerance programming and highlight antigen-presenting cell reprogramming as a promising design principle for immunoregulatory biomaterials in inflammatory heart disease.