Browning of fatty infiltration in rotator cuff tears using novel nanotherapeutics for improved healing, regeneration, and functional outcomes - PROJECT SUMMARY/ABSTRACT Rotator cuff (RC) tears are a leading cause of shoulder disability and often lead to muscle degeneration characterized by fatty infiltration (FI) and atrophy. These degenerative changes, most notably in the supraspinatus muscle, impair both muscle function and regenerative potential, and are major contributors to poor outcomes following surgical repair. Critically, once established, FI and atrophy are largely irreversible and significantly limit recovery. Currently, there are no therapies that specifically target FI or reverse its detrimental effects on muscle regeneration and function. White adipose tissue (WAT), the predominant fat type deposited during FI, primarily serves as an energy reservoir. In contrast, brown adipose tissue (BAT) and beige adipose tissue (bAT) - the latter arising from WAT through a process known as “fat browning” - are metabolically active and support tissue regeneration. Beige fat is characterized by the expression of uncoupling protein-1 (UCP-1), enabling thermogenesis and contributing to anti-inflammatory and pro-regenerative signaling. Prior studies suggest that bAT promotes myogenesis and improves muscle repair outcomes after RC tears. However, existing fat browning strategies in preclinical models often rely on gene editing, cell transplantation, or systemic pharmacological agents - approaches that are difficult to translate to clinical settings due to technical complexity, limited BAT availability in human tissues, and potential systemic side effects. To overcome these challenges, we developed a nanomedicine platform composed of lipid-coated mesoporous silica nanoparticles (LCMSN) loaded with forskolin (FSK), a natural compound known to induce fat browning. LCMSN/FSK enhances cellular uptake of FSK and promotes local WAT-to-bAT conversion. Our exciting preliminary data demonstrates LCMSN/FSK to induce thermogenic gene expression in-vitro and in-vivo. We hypothesize that intramuscular delivery of LCMSN/FSK will convert FI into bAT, thereby enhancing paracrine support for muscle regeneration and function following RC injury. We propose the following specific aims: Aim 1 will optimize the design of LCMSN/FSK to enhance delivery, retention, and fat browning within degenerating shoulder muscle. Aim 2 will investigate the effects of bAT on myotube formation, muscle cell performance, and macrophage polarization in in-vitro models developed in our lab. Aim 3 will determine the regenerative, functional, and anti-inflammatory effects of LCMSN/FSK in an in-vivo RC tear model with and without tendon repair. This work introduces a first- in-class nanotherapy that targets WAT in muscle to improve healing following RC tears. Successful completion of this project will establish a novel, translational approach to modulate intramuscular fat and enhance regenerative outcomes after tendon injury, addressing a significant unmet clinical need.
