Bone targeted microenvironment actuated engineered exosomes for precision therapy of IBD associated bone loss

Systemic bone loss is a frequent extraintestinal complication of inflammatory bowel disease (IBD) and can continue even when intestinal inflammation is clinically controlled. The steps linking gut inflammation to bone deterioration at distant sites are not fully defined. We found that interleukin-18 (IL-18) links intestinal inflammation to bone loss. In the gut, IL-18 supports mucosal repair and barrier maintenance. When circulating IL-18 remains elevated, it accumulates in bone-associated niches, shifts bone remodeling, and ultimately leads to bone loss. While IL-18 is a protective factor essential for intestinal repair and barrier homeostasis, its sustained systemic elevation leads to pathological accumulation in bone-associated niches, driving aberrant bone remodeling and bone loss. To address this challenge, we developed ExoBIP, a bone-targeted and microenvironment-actuated engineered exosome system. This platform enables site-specific IL-18 neutralization within inflamed bone tissues while preserving the physiological function of IL-18 in the gut. ExoBIP integrates the intrinsic pro-osteogenic properties of bone marrow mesenchymal stem cell derived exosomes with spatiotemporally controlled cytokine blockade, thereby simultaneously suppressing inflammation-driven bone resorption and supporting bone regeneration. In a chronic IBD-associated bone loss model, ExoBIP effectively restores bone mass, improves trabecular microarchitecture, and single-cell RNA sequencing showed that ExoBIP restores the marrow niche by increasing osteogenic cells and reducing inflammatory, cytotoxic CD8⁺ T cell programs. Collectively, this work establishes IL-18 as an actionable driver of IBD-induced bone loss and introduces a precision nanotherapeutic strategy for treating inflammation-induced skeletal complications, highlighting a generalizable paradigm for distal organ protection in chronic inflammatory diseases.