Poster X7 - Cargo-less Nano-Immunometabolic Therapy for Chronic Cardiac Fibrosis in Heart Failure

Introduction: Heart failure affects 6M patients annually in the U.S. with a 55% 5-year mortality rate. Pathological heart fibrosis, a major cause of heart failure, results from infiltration of hyper-activated T cells due to unresolved inflammation. Yet there is no therapeutic strategy targeting this immunological pathway. In this study we identified a nanoparticle formulation that upregulates arginase in macrophages. This upregulation is therapeutically beneficial in cardiac fibrosis as it suppresses T cells via arginine starvation.

Materials and

Methods: Cargo-less nano-immunometabolic modulators (NIMMs) targeting splenic macrophages were developed and optimized to alleviate chronic heart fibrosis utilizing high throughput screening. 144 formulations of poly(L-lactide-co-glycolide) (PLLGA)-based NIMMs were synthesized via nanoprecipitation, oil-in-water emulsion, and emulsion-diffusion employing various PLGA polymer molecular weights, L-to-G ratios, and surfactants. In vitro macrophage uptake and arginase upregulation was examined to identify the lead formulation. The biodistribution of the lead formulation was investigated, and the therapeutic outcomes were assessed in vitro using T cell culture and in vivo with two mice heart failure models.

Results, Conclusions, and Discussions: A multiple linear regression model was established using the screening data, which indicated that the use of “eat-me” signal phospholipids as surfactants significantly improved macrophage uptake and arginase upregulation. Primary murine macrophages retreated with the leading NIMM22 formulation (diameter 102.8±33.9 nm) showed a dose-dependent T cell suppression in vitro. This effect was abrogated when an arginase inhibitor was administered synergistically with NIMM22. Intravenous administration of NIMM22 to mice showed at least 3.6-fold higher accumulation in the spleen, which is the key organ driving chronic heart fibrosis and source of T cell infiltration. Furthermore, NIMM22 was tested in various mouse heart injury models. NIMM22 restored the levels of splenic effector and regulatory T cells in injured mice to non-injured levels, while reducing cardiac fibrosis and restoring ejection fraction. Collectively, this study presents NIMM22, a PLLGA-based nanoparticle formulation selected through high throughput screening and statistical modeling. NIMM22 targets splenic macrophages, reduces heart fibrosis and restores cardiac function, addressing the gap of fibrosis treatment aiming at upstream immunological pathways.

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