Targeted IL-4 nanoparticles for osteal macrophages modulation in osteoporosis

Osteoporosis (OP) is a chronic disease that compromises bone health. It is characterized by a disruption of bone tissue homeostasis, resulting in reduced bone mineral density and an increased risk of fractures. This enhanced fracture risk is associated with an elevated osteoclastic-to-osteoblastic activity ratio, reflecting excessive bone resorption relative to formation. Interleukin-4 (IL-4) is an immunomodulatory cytokine known to suppress osteoclast differentiation and influence the fate of osteal macrophages, cells that play a supportive role in bone resorption. Consequently, targeted IL-4 delivery aimed at modulating osteal macrophages represents a promising therapeutic strategy. This study explores the use of computational modelling-designed, mannose-functionalized lipid-polymer hybrid nanoparticles (LPNPs) for the targeted delivery of IL-4. Fluorescence cross-correlation spectroscopy (FCCS) and transmission electron microscopy images confirmed the core-shell structure and surface functionalization of the LPNPs, which are engineered for macrophage targeting. Confocal microscopy and flow cytometry revealed efficient cellular uptake of LPNPs through macropinocytosis. Our findings demonstrate that these LPNPs successfully deliver functional IL-4 to macrophages, leading to reduced IL-8 secretion and increased IL-10 production. This shift suggests a phenotypic modulation toward an anti-inflammatory state, potentially inhibiting osteoclast differentiation. Overall, the local administration of the developed systems can be a promising therapeutic approach for the management of osteoporosis.