Reprogramming of Myeloid Responses to Volumetric Muscle Loss via Engineered Protein Nanoparticles

The acute loss of muscle tissue from trauma or surgery or volumetric muscle loss (VML) is a significant injury that results in chronic and sustained inflammatory responses that in turn impinge on recovery of neuromuscular function. Understanding and manipulating the immune response to volumetric muscle loss thus hold promise for limiting tissue damage and improving regenerative outcomes. Herein, we analyzed the monocyte and macrophage response to volumetric muscle loss injuries that result in fibrosis or regeneration and observed increased numbers of total immune cells, pro-inflammatory monocytes and macrophages, and scar-associated macrophages for VML injuries that result in fibrosis. Administration of the AMPK agonist AICAR reduced neutrophils and macrophages post-VML injury. Since AICAR possesses poor bioavailability, synthetic protein nanoparticles containing AICAR were created and showed strong uptake by immune cells after injury. Treatment of VML injuries with synthetic protein nanoparticles containing AICAR showed minimal trafficking to other distal tissues and manipulation of macrophage phenotypes through phagocytosis and inflammatory signaling to other cell types. These results establish a paradigm through which immune dysfunction can be targeted and controlled after volumetric muscle loss.