Bone marrow-targeted delivery of canonical lipolytic receptor agonists via neutrophil hitchhiking reverses osteoporosis

Abstract Current osteoporosis therapies fail to fully restore bone mass because of insufficient targeting of the bone marrow microenvironment. Here, we report a cell-mediated delivery platform that leverages senescent neutrophils to specifically transport canonical lipolytic receptor (CLR) agonists to bone marrow adipose tissue (BMAT). Using both ovariectomy-induced and aged osteoporosis mouse models, we demonstrated that systemic CLR activation significantly reduces BMAT volume while improving trabecular bone structure but at the cost of inducing systemic lipolysis and metabolic disturbances. To overcome these limitations, we developed CL316243(CL)-loaded nanoparticles delivered by senescent neutrophils (CL-NPs@NEs), which exhibited greater bone marrow accumulation than free drug. CL-NPs@NEs treatment led to remarkable bone mass recovery without causing peripheral fat loss or metabolic complications. Combining neutrophil-delivered CL and parathyroid hormone further enhanced therapeutic efficacy. Our findings establish senescent neutrophils as effective drug carriers for bone marrow-targeted therapy and reveal that CLR agonism is a viable strategy to remodel the adipocyte-rich bone marrow microenvironment. Targeted modulation of marrow adipose tissue combined with the osteoanabolic agent teriparatide holds promise for superior bone microarchitecture reconstruction and bone quality improvement in osteoporosis.