Targeted delivery of senolytic drugs using macrophage membrane-camouflaged magnetic nanoparticles inhibits endplate sclerosis

INTRODUCTION: Low back pain (LBP) is a prevalent cause of disability worldwide. A crucial mechanism underlying LBP is that senescent-like macrophages induce endplate sclerosis by coupling angiogenesis-osteogenesis through IL-10. Then, the osteoclasts attract sensory innervation to perceive pain during endplate sclerosis. Therefore, targeted clearance of senescent-like macrophages is expected to be a new direction for LBP treatment. OBJECTIVES: In light of the side effects of systemic application of senolytic drugs, we propose to construct a targeted drug delivery system to accurately remove senescent-like macrophages in degenerating endplates. METHODS: In this study, iron oxide nanoparticles (Fe₃O₄ NPs) and the senolytic drug ABT-263 were co-encapsulated in PLGA to form magnetic nanospheres (MS@ABT), then coated with macrophage membranes (MM@MS@ABT), thus a drug-loaded delivery system with improved dual targeting ability of magnetism and inflammatory microenvironments was generated. In vivo and ex vivo imaging studies demonstrated that MM@MS@ABT aggregated at the designated mouse lumbar spine instability (LSI) modeling site. RESULTS: In vivo and in vitro findings showed that senescent-like macrophages were effectively eliminated by MM@MS@ABT, thereby inhibiting the expression and secretion of IL-10 from senescent-like macrophages. This reduced CD31⁺Emcn⁺ angiogenesis, and ultimately alleviated endplate sclerosis. CONCLUSION: Together, MM@MS@ABT exhibits a dual-targeting ability to aggregate near degenerated endplates and release senolytic drugs precisely to eliminate senescent-like macrophages in the endplates of LSI mice. It represents a potentially effective strategy for the treatment of LBP.